Compositions and Methods for Treating CNS Disorders

ABSTRACT

The present disclosure is drawn to compositions and methods for treating CNS disorders. In one embodiment, an oral pharmaceutical composition can comprise a therapeutically effective amount of pregn-4-ene-3,20-dione; and a pharmaceutically acceptable carrier that provides formation of either 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or both in an amount sufficient to treat a CNS disorder when orally administered to a subject. In another embodiment, a method of treating a CNS disorder can comprise orally administering to a subject, a therapeutically effective amount of pregn-4-ene-3,20-dione that provides an amount of GABA receptor binding pregn-4-ene-3,20-dione metabolites that is sufficient to treat the CNS disorder. In another embodiment, a method of treating a CNS disorder can comprise orally administering to the subject, a therapeutically effective amount of pregn-4-ene-3,20-dione that provides an amount of 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or both that is sufficient to treat the CNS disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

This nonprovisional utility patent application is a continuation of andclaims the benefit under 35 USC § 120 to co-pending U.S. patentapplication Ser. No. 17/314,883 filed May 7, 2021 and anticipated toissue on May 24, 2022 as U.S. Pat. No. 11,337,987, and which isexpressly incorporated herein its entirety by this reference.

FIELD OF THE DISCLOSURE

The present disclosure relates to compositions, dosage forms andregimens, and methods of treating a subject with a central nervoussystem (CNS) disorder. Accordingly, this disclosure involves the fieldsof chemistry, pharmaceutical sciences, medicine, and other healthsciences.

BACKGROUND

CNS disorders are neurological disorders that can affect the structureor function of the brain or spinal cord. CNS disorders can have variouscauses including trauma, infections, degeneration, structural defects,tumors, autoimmune disorders, and strokes. Some examples includeaddiction, attention deficit hyperactivity disorder (ADHD), autism,epilepsy, multiple sclerosis, depression, anxiety, and the like. A widerange of treatments have been tried for CNS disorders ranging fromsurgery to neural rehabilitation to prescription medication. Depressionis a mood disorder that can cause persistent feelings of sadness andanhedonia. Specific depression conditions such as Major DepressiveDisorder or Clinical Depression, affect an individual feels, thinks andbehaves, and can lead to a variety of further emotional and physicalproblems.

Perinatal depression or Postpartum depression (PPD) is a form of a majordepression disorder affecting expectant and new mothers and ischaracterized by extreme sadness, difficulty bonding with the infant,low energy, anxiety, crying episodes, irritability, feelings of guiltand/or inadequacy, thoughts of self- and/or infant-harm, and changes insleeping or eating patterns. Onset of PPD can range from the thirdtrimester of pregnancy through about 4 weeks following childbirth.Current statistics show that PPD affects about 10% to 15% of women afterchildbirth. Treatment for PPD has included cognitive behavioral therapy,interpersonal therapy, antidepressant medication, electroconvulsivetherapy, and light aerobic exercise. However, some studies haveindicated that many antidepressant medications are insufficientlyeffective in treating PPD. Further, traditional antidepressants haveslow onset, taking weeks to months to reach full efficacy. Therefore,better ways of treating PPD in general continue to be sought.

To-date an injectable (continuous intravenous infusion) brexanalone(i.e. allopregnalone) product marketed under the name ZULRESSO® is theonly product approved in the United States for the indication of PPD inwomen of childbearing age. However, treatment requires hospitalizationand the patient needs to be administered and monitored closely by ahealth care provider in a recognized health care setting under a riskevaluation and mitigation strategy (REMS). In addition to privacy andsocial stigma issues, the ZULRESSO® treatment protocol requires apatient's admission to a perinatal inpatient unit, which is demanding toa mother when she is still bonding with her newborn. Additional issueswith ZULRESSO® treatment include the lengthy duration of therapy, needlephobia, vascular access injection site infection risk, potentialrepetitive needle sticks to find veins, etc. Furthermore, in view of itsnon-oral administration form, treatment with ZULRESSO′ also presentscost, access, and logistics issues as well the need for a healthcarefacility to spend significant time preparing to become treatment ready.Therefore, a significant unmet need exists for an oral composition andmethods to treat a CNS depression disorder such as PPD. Utilizingpregn-4-ene-3,20-dione as an oral option to treat depression has beenchallenging either due to difficulty generating adequate serum PAM(Positive Allosteric Modulator of GABA_(A) receptor (PAM) levels causedby ineffective dose and dosing regimens for oral delivery or becausesuch compositions are typically formulated with a crystalline form ofthe active agent with deficient characteristics resulting insub-therapeutics serum levels of PAMs.

SUMMARY

The present disclosure encompasses compositions and oral dosage formsand regimens including pregn-4-ene-3,20-dione and related methods. Thecompositions and oral dosage forms can be formulated to include atherapeutically effective amount of pregn-4-ene-3,20-dione and apharmaceutically acceptable carrier. In one aspect, the pharmaceuticallyacceptable carrier of the composition or dosage form can provideformation of either 3α-OH-5β-pregnan-20-one, or 3α-OH-5α-pregnan-20-oneor both, collectively referred to as positive allosteric modulators(PAMs or 3α metabolites) of GABA_(A) receptor, in an amount sufficientto treat a CNS depression disorder when orally administered to asubject. In another aspect, the composition or dosage form can includepregn-4-ene-3,20-dione in a form that enhances, increases, or maximizesformation of either 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one,or both when orally administered to a subject. In another aspect, thecomposition or dosage form can include pregn-4-ene-3,20-dione with acarrier and/or in a form that modulates formation of either3β-OH-5α-pregnan-20-one, or 3β-OH-5β-pregnan-20-one, or both,collectively referred to as negative allosteric modulators (NAMs) ofGABA_(A) receptor, when orally administered to a subject. For example,in one aspect, the pregn-4-ene-3,20-dione can be formulated with acarrier that when orally administered to a subject increases formationof either 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or bothas compared to an equivalent amount of pregn-4-ene-3,20-dione utilizinga purpose-inadequate carrier or compositions comprising micronizedpregn-4-ene-3,20-dione when orally administered to the subject.

In yet another embodiment, there is provided compositions and oraldosage forms that include a therapeutically effective amount ofpregn-4-ene-3,20-dione and a pharmaceutically acceptable carrier thatprovides increased formation of gamma aminobutyric acid (GABA) receptorbinding/modulating PAMs as compared to an equivalent amount ofpregn-4-ene-3,20-dione utilizing a purpose-inadequate carrier orcompositions comprising micronized pregn-4-ene-3,20-dione when orallyadministered the subject.

In one embodiment, the composition can be formulated as an oral dosageform that has from about 10 mg to about 400 mg ofpregn-4-ene-3,20-dione. In one aspect, the oral dosage form can be asolid, liquid, a semi-liquid or semi solid, a syrup, an emulsion, adispersion, a suspension, a capsule, a sprinkle, a tablet, a chew, or adrink. In one aspect, some dosage forms can be administered by aninjectable for infusion to a subject.

In yet another embodiment, a method of treating a CNS depressiondisorder in a subject can include orally administering a therapeuticallyeffective amount of pregn-4-ene-3,20-dione to the subject. In oneaspect, the therapeutically effective amount of pregn-4-ene-3,20-dionecan provide an amount of 3α-OH-5α-pregnan-20-one, or3α-OH-5β-pregnan-20-one, or both that is sufficient to treat the CNSdepression disorder. In another aspect, the therapeutically effectiveamount of pregn-4-ene-3,20-dione can be in a form that provides atherapeutically effective amount of either 3α-OH-5α-pregnan-20-one, or3α-OH-5β-pregnan-20-one, or a combination thereof for treating the CNSdepression disorder in the subject. In yet another aspect, thepregn-4-ene-3,20-dione can be combined with a carrier that is sufficientto provide a therapeutically effective amount of either3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or a combinationthereof for treating the CNS depression disorder in the subject. In yetanother aspect, the pregn-4-ene-3,20-dione can be combined with acarrier that is sufficient to provide a therapeutically effective amountof either 3β-OH-5α-pregnan-20-one, or 3β-OH-5β-pregnan-20-one, or bothto modulate effects of either 3α-OH-5α-pregnan-20-one, or3α-OH-5β-pregnan-20-one or both for treating the CNS depression disorderin the subject.

In yet another aspect, the pregn-4-ene-3,20-dione can be combined with acarrier that is sufficient to provide a therapeutically effective amountof either 3β-OH-5α-pregnan-20-one, or 3β-OH-5β-pregnan-20-one, or bothto modulate effects of either 3α-OH-5α-pregnan-20-one, or3α-OH-5β-pregnan-20-one or both for resulting in desired CNS activity inthe subject.

BRIEF DESCRIPTION OF THE DRAWINGS

Features and advantages of invention embodiments will be apparent fromthe detailed description which follows, taken in conjunction with theaccompanying drawings, which together illustrate, by way of example,features of the disclosure; and wherein:

FIG. 1 depicts metabolic pathways of pregn-4-ene-3,20-dione inaccordance with an example;

FIG. 2 depicts plots of the release profile of pregn-4-ene-3,20-dionecontaining oral dosage forms in accordance with certain inventionembodiments as compared to a dosage form containing 100 mg micronizedpregn-4-ene-3,20-dione suspended in oil. The % release ofpregn-4-ene-3,20-dione was measured using a USP Type I dissolutionapparatus in 900 mL of deionized water with 2.0% (w/v) of sodium laurylsulfate (SLS) at 100 rpm at 37° C.; and

FIG. 3 depicts plots of the release profile of pregn-4-ene-3,20-dionecontaining oral dosage forms in accordance with certain inventionembodiments. The % release of pregn-4-ene-3,20-dione was measured usinga USP Type II dissolution apparatus in 900 mL of deionized water with0.25% (w/v) of SLS at 75 rpm at 37° C.

Reference will now be made to the exemplary embodiments illustrated, andspecific language will be used herein to describe the same. It willnevertheless be understood that no limitation of the scope of thedisclosure is thereby intended.

DETAILED DESCRIPTION

Before invention embodiments are described, it is to be understood thatthis disclosure is not limited to the particular structures, processsteps, or materials disclosed herein, but is extended to equivalentsthereof as would be recognized by those ordinarily skilled in therelevant arts. It should also be understood that terminology employedherein is used for the purpose of describing particular examples orembodiments only and is not intended to be limiting.

Furthermore, the described features, structures, or characteristics canbe combined in any suitable manner in one or more embodiments. In thefollowing description, numerous specific details are provided, such asexamples of compositions, dosage forms, treatments, etc., to provide athorough understanding of various invention embodiments. One skilled inthe relevant art will recognize, however, that such detailed embodimentsdo not limit the overall inventive concepts articulated herein but aremerely representative thereof.

Definitions

It should be noted that, the singular forms “a,” “an,” and, “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to “an excipient” includes reference to oneor more of such excipients, and reference to “the carrier” includesreference to one or more of such carriers.

As used herein, the terms “treat,” “treatment,” or “treating” and thelike refers to administration of a therapeutic agent to a subject who iseither asymptomatic or symptomatic. In other words, “treat,”“treatment,” or “treating” can refer to the act of reducing oreliminating a condition (i.e., symptoms manifested), or it can refer toprophylactic treatment (i.e., administering to a subject not manifestingsymptoms in order to prevent their occurrence). Such prophylactictreatment can also be referred to as prevention of the condition,preventative action, preventative measures, and the like.

As used herein, the terms “therapeutic agent,” “active agent,” and thelike can be used interchangeably and refer to an agent or substance thathas measurable specified or selected physiologic activity whenadministered to a subject in a significant or effective amount. It is tobe understood that the term “drug” is expressly encompassed by thepresent definition as many drugs and prodrugs are known to have specificphysiologic activities. These terms of art are well-known in thepharmaceutical and medicinal arts. Further, when these terms are used,or when a particular active agent is specifically identified by name orcategory in this written description, it is understood that suchrecitation is intended to include express support for the active agentper se, as well as pharmaceutically acceptable salts, esters orcompounds significantly related thereto, including without limitation,prodrugs, isomers, and the like.

As used herein, the terms “formulation” and “composition” are usedinterchangeably and refer to a mixture of two or more compounds,elements, or molecules. In some aspects, the terms “formulation” and“composition” may be used to refer to a mixture of one or more activeagents with a carrier or other excipients. Furthermore, the term “dosageform” can include one or more formulation(s) or composition(s) providedin a format for administration to a subject. For example, an “oraldosage form” can be suitable for administration to a subject's mouth. A“topical dosage form” can be suitable for administration to a subject'sskin by rubbing, etc.

As used herein, “pharmaceutically acceptable carrier” or “carrier” areused interchangeably and refer to a pharmaceutically acceptable agent oringredient that can be combined with an active agent as part of acomposition or dosage form. In some aspects, pharmaceutically acceptablecarriers can impact the form or behavior of an active agent. Forexample, in some aspects, a pharmaceutically acceptable carrier can becapable of fully or partially dissolving or solubilizing an active agent(e.g., pregn-4-ene-3,20-dione) in a pharmaceutical composition orenabling a non-crystalline amorphous form of the active agent. Further,in some aspects, the carrier can impact or control the properties andperformance of the composition or dosage form. For example, in someaspects, a carrier can impact or control the pharmacokinetic performanceor profile (e.g. release rate and/or extent of release of the activeagent) of the composition and/or the dosage form.

As used herein, a “semi-liquid” or “semi-solid” corresponds to apartially solubilized active agent and a “liquid” corresponds to a fullysolubilized active agent at room temperature. “Solid” corresponds to afully solid active agent at room temperature.

As used herein, a “subject” refers to a mammal that may benefit from theadministration of a drug composition, dosage form or dosage regimen, ormethod disclosed herein. Examples of subjects include humans, and mayalso include other animals such as horses, pigs, cattle, dogs, cats,rabbits, and aquatic mammals. In one specific aspect, a subject is ahuman. In another aspect, the subject is a female. In another aspect,the subject is a female is of childbearing age. In another aspect thefemale as delivered a baby within the last 12 months. In another aspect,the subject is male.

As used herein, “in need of treatment” and the like refers to a subjectthat has a disease, condition, or disorder or is suspected of having thedisease, condition, or disorder according to various diagnostic criteriatypically used in practice, or desires treatment or is indicated fortreatment. Thus, “in need of treatment” can include the operation ofidentifying a subject in need of treatment.

As used herein, “identifying a subject in need of treatment” can includethe operation of obtaining a biological sample from the subject anddetermining the level of one or more biomarkers as described herein,assessing a biological sample obtained from said subject, performing animaging analysis on the subject, assessing one or more clinicalcharacteristics of said subject (e.g., assessing symptoms or overtsymptoms), or a combination thereof.

As used herein, the terms “illness,” “disease,” “condition,” “symptom”,and “disorder” can be used interchangeably and refer to an abnormalityor incorrect functioning of any part, group, or system of a subject'sphysiology regardless of the causality thereof. For example, a mentalillness or emotional disorder can be caused by environmental factors,genetic factors, physiologic events, past experiences, and otherinfluences or combinations thereof.

As used herein, an “acute” condition refers to a condition that candevelop rapidly and have distinct symptoms needing urgent or semi-urgentcare. By contrast, a “chronic” condition refers to a condition that istypically slower to develop and lingers or otherwise progresses overtime. Some examples of acute conditions can include without limitation,an asthma attack, bronchitis, a heart attack (myocardial infarction),pneumonia, and the like. Some examples of chronic conditions can includewithout limitation, arthritis, diabetes, hypertension, high cholesterol(hyperlipidemia), and the like.

The terms “serum levels,” “serum amounts”, “serum concentrations,”“plasma levels,” “plasma concentrations,” “blood levels,” and “bloodconcentrations” and the like can be used interchangeably herein andrefer to the total amount of an identified analyte (e.g. identifiedmetabolite or active agent), including free, bioavailable, and boundfractions in a subject's blood. For example, “serum3α-OH-5α-pregnan-20-one” or “serum 3α-OH-5α-pregnan-20-one levels” or“serum 3α-OH-5α-pregnan-20-one concentration” or “plasma3α-OH-5α-pregnan-20-one concentration” or “3α-OH-5α-pregnan-20-oneconcentration in the blood” refer the total 3α-OH-5α-pregnan-20-oneconcentration which is the sum of the 3α-OH-5α-pregnan-20-one fractionspresent including substantially free and bound 3α-OH-5α-pregnan-20-oneconcentrations. Likewise, the terms “serum 3α-OH-5β-pregnan-20-one” or“serum 3α-OH-5β-pregnan-20-one levels,” “serum 3α-OH-5β-pregnan-20-oneconcentration,” “plasma 3α-OH-5β-pregnan-20-one concentration,” or“3α-OH-5β-pregnan-20-one concentration in the blood” are usedinterchangeably and refer the total 3α-OH-5β-pregnan-20-oneconcentration which is the sum of the 3α-OH-5β-pregnan-20-one fractionspresent including substantially free and bound 3α-OH-5β-pregnan-20-oneconcentrations. It should be understood that in this writtendescription, such terms provide express support for total analyte oragent levels, as well as for the various applicable fractions thereof,including bioavailable, bound, and substantially free fractions. Unlessotherwise specified, these values are “observed” concentrations oramounts without adjusting or correcting for the base-line serum levelsin the subject(s). As with any bio-analytical measure, for increasedconsistency, the method employed to measure initial serum levels shouldbe consistent with the method used to monitor and re-measure serumlevels during clinical testing and therapy for a subject. As usedherein, the term “C_(avg),” refers to an average serum concentrationlevel for time 0 to t (e.g. average daily serum concentration level,daily C_(avg), is calculated as ratio of AUC₀₋₂₄/24 hours) and the term“C_(max),” refers to a maximum serum concentration level post singledose administration.

Serum neurosteroid measurements for pregn-4-ene-3,20-dione, and its PAMor NAM metabolites based on an immunoassay are not accurate because theassay is typically not specific to the target analyte. To measure thetarget analyte, the assay should be based on chromatography-combinedmass spectrometry method (e.g. LC-MS/MS or GC-MS), which can providereliable data to assess the true pharmacokinetic and pharmacodynamicpotential of pregn-4-ene-3,20-dione and its PAM and NAM metabolites.Consequently, data and results related to oral pregn-4-ene-3,20-dioneand its neurosteroid, PAM (e.g., 3α-OH-5α-pregnan-20-one,3α-OH-5β-pregnan-20-one) or NAM (e.g., 3β-OH-5α-pregnan-20-one,3β-OH-5β-pregnan-20-one) metabolites are only reliable with respect tolevels of neurosteroid generation or the adequacy of neurosteroid levelsfor desirable GABA receptor modulation when determined by analyticalprocedures that are amenable to the individual analyte separation stepfor specificity and accuracy, such as for liquid or gas chromatography,liquid chromatography-tandem mass spectrometry, or gaschromatography-mass spectrometry (LC-MS/MS or GC-MS).

In one aspect the pharmacokinetic values (e.g. serum concentrations,computed ratios) of an analyte of interest (e.g. pregn-4-ene-3,20-dioneor a PAM, or a NAM), derived from the present compositions and methodsare based on LC-MS/MS or GC-MS measurements.

As use herein with respect to physiologic levels of a given substance,the term “baseline” refers to a level or concentration of the substance,such as analyte of interest (e.g. pregn-4-ene-3,20-dione or a PAM, or aNAM), in a subject prior to administration of an active agent. Forexample, the baseline level of pregn-4-ene-3,20-dione in a subject wouldthe subject's pregn-4-ene-3,20-dione serum level prior (e.g., justprior) to the commencement of pregn-4-ene-3,20-dione treatment.

The term “oral administration” represents any method of administrationin which an active agent can be administered by swallowing, chewing,sucking, or drinking of the composition or dosage form. Oraladministration can be intended for enteral delivery of an active agentor transmucosal delivery of the active agent. In some embodiments, thecomposition and dosage forms of the current disclosure can be admixedwith food or drink prior to being orally consumed or can be otherwiseco-administered with food.

As used herein, the terms “release” and “release rate” are usedinterchangeably to refer to the discharge or liberation ofpregn-4-ene-3,20-dione from the composition or dosage form into asurrounding environment such as an aqueous medium either in vitro or invivo.

As used herein, the terms “dissolution” refers to solubilization of thepregn-4-ene-3,20-dione into a surrounding environment such as an aqueousmedium either in vitro or in vivo.

In some aspects, the release of the drug may be controlled release. Asused herein, the term “controlled release” represents the release of thedrug from the dosage form according to a predetermined profile. In someaspects, the controlled release selected can be, accelerated,intermediate, delayed, extended, sustained, pulsatile, gastric, entericor colonic. Accelerated released may be obtained by for instance anincreased rate of release of the drug, an increased susceptibility tometabolism in the Gastro-intestinal (GI) tract, and combinationsthereof. In another aspect, combinations of the aforementioned releaseprofiles may be used in order to achieve specific delivery results, suchas an immediate release followed by a delayed and/or a sustained releaseof the active agent.

As used herein, a “dosing regimen” or “regimen” such as an “initialdosing regimen” or “starting dose” or a “maintenance dosing regimen”refers to how, when, how much, and for how long a dose of thecompositions or dosage forms of the present disclosure can beadministered to a subject. For example, an initial or starting doseregimen for a subject may provide for a total daily dose of from about15 mg to about 1500 mg administered in two divided doses at least 12hours apart (e.g., once with breakfast and once with dinner) with mealsrepeated daily for 30 days.

As used herein, “daily dose” refers to the amount of active agent (e.g.,pregn-4-ene-3,20-dione) administered to a subject over a 24-hour periodof time. The daily dose can be administered one or more administrationsduring the 24-hour period. In one embodiment, the daily dose providesfor two or three or four or six or eight administrations in a 24-hourperiod. With this in mind, an “initial dose” or initial daily dose”refers to a dose administered during the initial regimen or period of adosing regimen.

As used herein, an “effective amount” or a “therapeutically effectiveamount” of a drug refers to a non-toxic, but sufficient amount of thedrug, to achieve therapeutic results in treating a condition for whichthe drug is known to be effective. It is understood that variousbiological factors may affect the ability of a substance to perform itsintended task. Therefore, an “effective amount” or a “therapeuticallyeffective amount” may be dependent in some instances on such biologicalfactors. Further, while the achievement of therapeutic effects may bemeasured by a physician or by other qualified medical personnel usingevaluations known in the art, it is recognized that individual variationand response to treatments may make the achievement of therapeuticeffects a somewhat subjective decision. The determination of aneffective amount is well within the ordinary skill in the art ofpharmaceutical sciences and medicine. See, for example, Meiner andTonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographsin Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein byreference.

As used herein “single unit” when used to describe dosing of a subjectrefers to the dosage form being a single dosage form, e.g. a singletablet, capsule, pump or squirt of gel or solution, etc. In contrast,“multiple unit” when used to describe dosing of a subject refers to thedosage including two or more dosage forms, e.g. 2 capsules, 3 tablets,2-4 pumps or squirts, etc. It is noteworthy that multiple unit dosageforms generally will be the same type of dosage forms (i.e. tablet orcapsule) but are not required to be the same dosage form type.

As used herein, the term “meal” refers to any of the regular occasionsin a day when a reasonably large amount of food is eaten, such asbreakfast, lunch, or dinner.

As used herein, the term “Tmax” refers to mean or median time to peakserum level post single dose administration.

As used herein, the term “micronized administration” refers toadministration of crystalline micronized pregn-4-ene-3,20-dionedispersed in a composition comprising edible oil and lecithin or in acomposition comprising monohydrous lactose.

In this disclosure, “comprises,” “comprising,” “containing” and “having”and the like can have the meaning ascribed to them in U.S. Patent lawand can mean “includes,” “including,” and the like, and are generallyinterpreted to be open ended terms. The terms “consisting of” or“consists of” are closed terms, and include only the components,structures, steps, or the like specifically listed in conjunction withsuch terms, as well as that which is in accordance with U.S. Patent law.“Consisting essentially of” or “consists essentially of” have themeaning generally ascribed to them by U.S. Patent law. In particular,such terms are generally closed terms, with the exception of allowinginclusion of additional items, materials, components, steps, orelements, that do not materially affect the basic and novelcharacteristics or function of the item(s) used in connection therewith.For example, trace elements present in a composition, but not affectingthe compositions nature or characteristics would be permissible ifpresent under the “consisting essentially of” language, even though notexpressly recited in a list of items following such terminology. Whenusing an open-ended term, like “comprising” or “including,” in thiswritten description it is understood that direct support should beafforded also to “consisting essentially of” language as well as“consisting of” language as if stated explicitly and vice versa.

The terms “first,” “second,” “third,” “fourth,” and the like in thedescription and in the claims, if any, are used for distinguishingbetween similar elements and not necessarily for describing a particularsequential or chronological order. It is to be understood that any termsso used are interchangeable under appropriate circumstances such thatthe embodiments described herein are, for example, capable of operationin sequences other than those illustrated or otherwise described herein.Similarly, if a method is described herein as comprising a series ofsteps, the order of such steps as presented herein is not necessarilythe only order in which such steps may be performed, and certain of thestated steps may possibly be omitted and/or certain other steps notdescribed herein may possibly be added to the method.

Occurrences of the phrase “in one embodiment,” or “in one aspect,”herein do not necessarily all refer to the same embodiment or aspect.

As used herein, comparative terms such as “increased,” “decreased,”“better,” “worse,” “higher,” “lower,” “enhanced,” “improved,”“maximized,” “minimized,” and the like refer to a property of a device,component, composition, biologic response, biologic status, or activitythat is measurably different from other devices, components,compositions, biologic responses, biologic status, or activities thatare in a surrounding or adjacent area, that are similarly situated, thatare in a single device or composition or in multiple comparable devicesor compositions, that are in a group or class, that are in multiplegroups or classes, or as compared to an original (e.g. untreated) orbaseline state, or the known state of the art. For example, acomposition or dosage form comprising pregn-4-ene-3,20-dione that“increases” 3α-OH-5α-pregnan-20-one or 3α-OH-5β-pregnan-20-one serumlevels provides a 3α-OH-5α-pregnan-20-one or 3α-OH-5β-pregnan-20-oneserum level in a subject that is elevated as compared to a serum levelat a previous point in time, such as a baseline level (e.g., prior totreatment), or as compared to an earlier treatment with a different dose(e.g., lower dose). Alternatively, a composition or dosage form thatprovides an “increased” serum level of 3α-OH-5α-pregnan-20-one or3α-OH-5β-pregnan-20-one may provide such increase as compared to analternative known composition or dosage form e.g. compared to anequivalent amount of pregn-4-ene-3,20-dione utilizing apurpose-inadequate carrier or compositions comprising crystallinepregn-4-ene-3,20-dione in oil when orally administered the subject.

As used herein, the term “substantially” refers to the complete ornearly complete extent or degree of an action, characteristic, property,state, structure, item, or result. For example, an object that is“substantially” enclosed would mean that the object is either completelyenclosed or nearly completely enclosed. The exact allowable degree ofdeviation from absolute completeness may in some cases depend on thespecific context. However, generally speaking the nearness of completionwill be so as to have the same overall result as if absolute and totalcompletion were obtained. The use of “substantially” is equallyapplicable when used in a negative connotation to refer to the completeor near complete lack of an action, characteristic, property, state,structure, item, or result. For example, a composition that is“substantially free of” particles would either completely lackparticles, or so nearly completely lack particles that the effect wouldbe the same as if it completely lacked particles. In other words, acomposition that is “substantially free of” an ingredient or element maystill actually contain such item as long as there is no measurableeffect thereof.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint. Unless otherwise stated,use of the term “about” in accordance with a specific number ornumerical range should also be understood to provide support for suchnumerical terms or range without the term “about”. For example, for thesake of convenience and brevity, a numerical range of “about 50angstroms to about 80 angstroms” should also be understood to providesupport for the range of “50 angstroms to 80 angstroms.” Furthermore, itis to be understood that in this specification support for actualnumerical values is provided even when the term “about” is usedtherewith. For example, the recitation of “about” 30 should be construedas not only providing support for values a little above and a littlebelow 30, but also for the actual numerical value of 30 as well.

As used herein, a plurality of items, structural elements, compositionalelements, and/or materials may be presented in a common list forconvenience. However, these lists should be construed as though eachmember of the list is individually identified as a separate and uniquemember. Thus, no individual member of such list should be construed as ade facto equivalent of any other member of the same list solely based ontheir presentation in a common group without indications to thecontrary.

As used herein, the term “GABA” refers to gamma aminobutyric acid. GABAis the chief inhibitory neurotransmitter in the developmentally maturemammalian CNS. Its principal role is reducing neuronal excitabilitythroughout the nervous system. “GABA receptor” or “GABA receptors” referto receptors that are modulated by GABA. GABA_(A) receptors include anionotropic receptor and ligand-gated ion channel.

Concentrations, amounts, levels and other numerical data may beexpressed or presented herein in a range format. It is to be understoodthat such a range format is used merely for convenience and brevity andthus should be interpreted flexibly to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges or decimalunits encompassed within that range as if each numerical value andsub-range is explicitly recited. As an illustration, a numerical rangeof “about 1 to about 5” should be interpreted to include not only theexplicitly recited values of about 1 to about 5, but also includeindividual values and sub-ranges within the indicated range. Thus,included in this numerical range are individual values such as 2, 3, and4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as wellas 1, 2, 3, 4, and 5, individually. This same principle applies toranges reciting only one numerical value as a minimum or a maximum.Furthermore, such an interpretation should apply regardless of thebreadth of the range or the characteristics being described.

Reference throughout this specification to “an example” means that aparticular feature, structure, or characteristic described in connectionwith the example is included in at least one embodiment. Thus,appearances of the phrases “in an example” in various places throughoutthis specification are not necessarily all referring to the sameembodiment.

Clinical CNS disorder diagnosis and treatment including depression canbe assessed by at least one of the following ratingscales/questionnaires or similar measures that include measuringseverity of depression in individuals:

a. 17-item Hamilton Rating Scale for Depression (HAM-D)

The Hamilton Rating Scale for Depression is a 17-item questionnaire usedto diagnose depression, and as a guide to evaluate recovery andremission. The HAM-D is the most commonly used instrument for assessingsymptoms of depression and is administered by a trained physician.

b. Montgomery-Asberg Depression Rating Scale for Depression (MADRS)

The Montgomery-Asberg Depression Scale is a clinician-rated scale usedto examine the severity of depressive episodes in patients with mooddisorders. It consists of a clinical interview of 10 items that movesfrom broad questions to more detailed ones.

c. Columbia-Suicide Severity Rating Scale (C-SSRS)

The Colombia Suicide Severity Scale is a suicidal ideation and behaviorrating scale used to evaluate suicidality. The C-SSRS consists of abaseline assessment that evaluates the lifetime experiences of thesubject with suicidal ideation and/or behavior, and a post-baselineevaluation that focuses on suicidal risk since the last visit.

d. The Clinical Global Impression Scale of Severity (CGI-S)

CGI-S is an objective measure of the severity of patient's illness atthe time of assessment, relative to the clinician's past experience withpatients who have the same diagnosis.

e. The Clinical Global Impression Scale of Improvement (CGI-I)

CGI-I is a 7-item measure to assess the overall improvement of thepatient's illness, relative to the subject's baseline condition.

f. Hamilton Rating Scale for Anxiety (HAM-A)

HAM-A is a clinician-rated scale used to assess the severity of anxietysymptoms. The HAM-A consists of 14-items, each defined by a series ofanxiety symptoms, both psychic and somatic.

g. Edinburgh Postnatal Depression Scale (EPDS)

EPDS is a self-rated questionnaire used to identify postpartumdepression in outpatient, home visiting settings, or at the 6-8 weekexamination after delivery. The EPDS consists of 10 items that assessdepressive symptoms such as feeling of guilt, low energy, anhedonia,sleep disturbance, and suicidal ideation.

i. Maternal Postnatal Attachment Scale (MPAS)

MPAS is a self-rated questionnaire used to assess the mother-to-infantattachment. The MPAS consists of 19 items that evaluate the emotionalbond between the mother and the infant.

j. The Center for Epidemiologic Studies Depression Scale (CES-D)

CES-D is a 20-item measure that asks caregivers to rate how often overthe past week they experienced symptoms associated with depression, suchas restless sleep, poor appetite, and feeling lonely. Response optionsrange from 0 to 3 for each item (0=Rarely or None of the Time, 1=Some orLittle of the Time, 2=Moderately or Much of the time, 3=Most or AlmostAll the Time). Scores range from 0 to 60, with high scores indicatinggreater depressive symptoms. CES-D also provides cutoff scores (e.g., 16or greater) that aid in identifying individuals at risk for ClinicalDepression, with good sensitivity and specificity and high internalconsistency.

k. The Beck Depression Inventory (BDI)

BDI is a 21-item self-reporting questionnaire for evaluating theseverity of depression in normal and psychiatric populations. It relieson the theory of negative cognitive distortions as central todepression. Twenty-one items in BDI are consolidated from thoseobservations and ranked 0-3 for severity.

Generally, clinical CNS activity can be assessed thru monitoring some ofthe CNS vital signs, such as composite memory, verbal memory, visualmemory, psychomotor speed, reaction time, complex attention, cognitiveflexibility, processing speed, executive function, non-verbal reasoning,social acuity, sustained attention, working memory, simple motor speed.Alternatively, it may be assessed by monitoring occurrence of sleepinessor somnolence (measured by the Multiple Sleep Latency Test: MSLT, or theMaintenance of Wakefulness Test: MWT), dry mouth (measured by ClinicalOral Dryness Score: CODS), loss of consciousness (measured byElectroencephalography: EEG), dizziness (measured by vertigo,presyncope, disequilibrium, light-headedness, and a combination),fatigue (measured by Psychomotor Vigilance Task: PVT), hot flashes(measured by increases in heart rate, finger blood flow, mood ratingscale (e.g., sedation, calmness, contentedness), respiratory exchangeratio, skin temperature, and core body temperature, pulse oximetrymonitoring (measuring the saturation of oxygen in hemoglobin in arterialblood), and saccadic eye velocity measurements (measuring latency andsaccade pair ratios by infrared oculography).

DESCRIPTION

Reference will now be made in detail to preferred invention embodiments.While the embodiments will be described with particularity, the presentdisclosure is not limited to such embodiments. To the contrary, it isintended to cover alternatives, variants, modifications, and equivalentsas may be included within the spirit and scope of the disclosure.

An initial overview of technology embodiments is provided below, andthen specific technology embodiments are described in further detaillater. This initial summary is intended to aid readers in understandingthe technology more quickly but is not intended to identify key featuresor essential features of the technology nor is it intended to limit thescope of the claimed subject matter.

A pregnenedione is an unsaturated diketone derivative of a pregnane,such as budesonide and pregn-4-ene-3,20-dione. Pregnenediones are proneto high intestinal first pass effect. Some mucosal enzymes (e.g.,5α-reductases also known as 3-oxo-5α-steroid 4-dehydrogenases) areubiquitously expressed in various tissues including the intestinaltract. Therefore, the small intestine and liver have been implicated inpregnenedione metabolism because of high expression levels ofdrug-metabolizing enzymes. As illustrated in FIG. 1, two major enzymesgroups, 5α reductase and 5β reductase, are involved in the metabolism oforally administered pregn-4-ene-3,20-dione, producing5α-dihydroprogesterone (DHP) and 5β-DHP. This reduction metabolism isthe rate-limiting step in the generation of PAMs and NAMs. The firstmetabolism pathway results in production of: (a) 3α-OH-5α-pregnan-20-onevia 3α-hydroxysteroid dehydrogenase (HSD)-II/III enzyme, and (b)3β-OH-5α-pregnan-20-one via 3β-hydroxysteroid dehydrogenase (HSD)-II/IIIenzyme. The second pathway produces: (a) 3α-OH-5β-pregnan-20-one via3α-HSD and (b) 3β-OH-5β-pregnan-20-one via 3β-HSD enzyme.3α-OH-5α-pregnan-20-one, a PAM, is a potent positive modulator ofGABA_(A) receptor activity, but its 3 beta epimer,3β-OH-5α-pregnan-20-one activity on GABA_(A) receptors is deemed as aNAM and has been shown to modulate the effects of a PAM (e.g.,3α-OH-5α-pregnan-20-one). Also, 3α-OH-5β-pregnan-20-one, a PAM, is knownas a potent positive modulator of GABA_(A) receptor activity, but its 3beta epimer, 3β-OH-5β-pregnan-20-one is deemed as a NAM and has beenshown to modulate the effects of PAM (e.g., 3α-OH-5β-pregnan-20-one).

Some of the neuro-modulatory and protective effects of3α-OH-5α-pregnan-20-one and/or 3α-OH-5β-pregnan-20-one may contribute tothe benefits and side effects of pregn-4-ene-3,20-dione administration.Specifically, 3α-OH-5α-pregnan-20-one and/or 3α-OH-5β-pregnan-20-one canproduce anticonvulsant, antidepressant, anxiolytic, and neuroprotectiveeffects in experimental animals as well as in tissues and cell cultures.Human data has been more contradictory, and several studies have beenconducted in an effort to evaluate the neuro-modulatory effects ofpregn-4-ene-3,20-dione and its metabolites.

Moreover, reported serum levels of neurosteroid, PAM and NAM,metabolites post administration using compositions and methods withpurpose-inadequate carrier or crystalline pregn-4-ene-3,20-dione orsub-therapeutic doses result in inadequate levels to effectively treatCNS depression disorders. Furthermore, previous oralpregn-4-ene-3,20-dione disclosures are directed towards reducing sideeffects in treating a non-CNS indications such as prevention ofendometrial hyperplasia in non-hysterectomized postmenopausal women whoare receiving conjugated estrogens or for use in secondary amenorrheasuch that the pregn-4-ene-3,20-dione composition and methods minimizesthe amount of serum 3α-OH-5α-pregnan-20-one and/or3α-OH-5β-pregnan-20-one; hence, the risk of related adverse effects.

Some efforts have been made in prior compositions to minimize therelease of pregn-4-ene-3,20-dione in the upper GI tract to preventconversion in the intestinal gut, wall, and flora in order to limit sideeffects from GABA active neurosteroids after oral administration ofpregn-4-ene-3,20-dione. However, there have been no compositions ormethods of administration directed towards generating adequate levels ofGABA_(A) receptor modulators for therapeutic utility: especially forhigher and faster production of the amount of serum3α-OH-5α-pregnan-20-one and/or 3α-OH-5β-pregnan-20-one. Such priorcompositions and methods use components that result in ineffectiveamount of serum 3α-OH-5α-pregnan-20-one and/or 3α-OH-5β-pregnan-20-one,or that have been formulated with crystalline pregn-4-ene-3,20-dionewith deficient characteristics.

Achieving desired serum 3α-OH-5α-pregnan-20-one and/or3α-OH-5β-pregnan-20-one levels or appropriate oral dose for efficacy forCNS depression indications has remained elusive, especially for unmetdisorders such as Major Depressive Disorder or peri-natal or post-partumdepression. The production of 3α-OH-5α-pregnan-20-one and/or3α-OH-5β-pregnan-20-one from oral pregn-4-ene-3,20-dione as a prodrughas been challenging for numerous reasons. For example, oralpregn-4-ene-3,20-dione as a prodrug has resulted in erratic neurosteroidlevels and inconsistent PD effects.

Thus, there remains an unmet need for compositions and methods thatenable generation of higher, faster, more reliable, and adequate levelsof 3α-OH-5α-pregnan-20-one and/or 3α-OH-5β-pregnan-20-one for treatingvarious CNS depression disorders whereby immediate generation andsubsequent effective absorption of 3α-OH-5α-pregnan-20-one and/or3α-OH-5β-pregnan-20-one is enabled for treating women of child-bearingage, and males. In some aspects, we have surprisingly found compositionsand methods effective to produce desirable levels of3α-OH-5α-pregnan-20-one and/or 3α-OH-5β-pregnan-20-one by inducingimmediate reduction of the prodrug in favor of high3α-OH-5α-pregnan-20-one and/or 3α-OH-5β-pregnan-20-one generation in theGI tract needed to treat CNS depression disorders. In one aspect we havesurprisingly found compositions and methods effective to producedesirable levels of 3α-OH-5α-pregnan-20-one and/or3α-OH-5β-pregnan-20-one without significant alteration of the desiredCNS activity due to 3β-OH-5α-pregnan-20-one and/or3β-OH-5β-pregnan-20-one. In yet another aspect, the present compositionsand methods comprise amounts of pregn-4-ene-3,20-dione with carriersthat is sufficient to provide effective amount(s) of either3β-OH-5α-pregnan-20-one, or 3β-OH-5β-pregnan-20-one, or3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or a combinationthereof for treating the CNS depression disorder in the subject.

In yet another aspect, the present compositions and methods compriseamounts of pregn-4-ene-3,20-dione with carriers that is sufficient toprovide effective amount(s) of either 3β-OH-5α-pregnan-20-one, or3β-OH-5β-pregnan-20-one, or 3α-OH-5α-pregnan-20-one, or3α-OH-5β-pregnan-20-one, or a combination thereof resulting in desiredCNS activity in the subject.

In some aspects, the present compositions and methods treat a CNSdisorder comprising depression. For example, a Major Depressive Disorderor perinatal depression or postpartum depression.

In one embodiment, pregn-4-ene-3,20-dione compositions and oral dosageforms can be formulated to provide amounts or peak levels of3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or both that aretherapeutically effective for treating a CNS disorder when orallyadministered to a subject. For example, in one aspect, the compositionsand oral dosage forms can include a pharmaceutically acceptable carrierthat provides formation of either 3α-OH-5α-pregnan-20-one, or3α-OH-5β-pregnan-20-one, or both in an amount sufficient to treat a CNSdisorder when orally administered to a subject.

In one embodiment, an oral pharmaceutical composition comprises anamount of pregn-4-ene-3,20-dione and a pharmaceutically acceptablecarrier, wherein said composition treats a CNS disorder in a subjectupon oral administration by providing at least one of the followingserum level ratios comprising:

-   -   C_(max)/dose of 3α-OH-5β-pregnan-20-one/pregn-4-ene-3,20-dione        of from about 5.0×10⁻⁸/ml to about 2.5×10⁻⁶/ml,    -   C_(max)/dose of 3α-OH-5α-pregnan-20-one/pregn-4-ene-3,20-dione        of from about 7.5×10⁻⁸/ml to about 2.5×10⁻⁶/ml, and    -   C_(max)/dose of (3α-OH-5α-pregnan-20-one and        3α-OH-5β-pregnan-20-one)/pregn-4-ene-3,20-dione of from about        1.3×10⁻⁷/ml to about 5.0×10⁻⁶/ml.        In one aspect, the analyte serum levels are measured using a        chromatography combined mass spectrometry method (e.g., LC-MS/MS        or GC-MS).

In another embodiment, an oral pharmaceutical composition comprises anamount of pregn-4-ene-3,20-dione and a pharmaceutically acceptablecarrier, wherein said composition treats a CNS disorder in a subjectupon oral administration by providing at least one of the followingvalues comprising:

-   -   a serum level C_(max) of 3α-OH-5α-pregnan-20-one of greater than        about 18 ng/ml,    -   a serum level C_(max) of 3α-OH-5β-pregnan-20-one of greater than        about 11 ng/ml,    -   a ratio of C_(max)/C_(max) of        3α-OH-5α-pregnan-20-one/pregn-4-ene-3,20-dione of from about 3.0        to about 50,    -   a ratio of C_(max)/C_(max) of        3α-OH-5β-pregnan-20-one/pregn-4-ene-3,20-dione of from about 3.0        to about 50, and    -   a ratio of C_(max)/C_(max) of (3α-OH-5α-pregnan-20-one and        3α-OH-5β-pregnan-20-one)/pregn-4-ene-3,20-dione of from about 5        to about 100.

In one aspect, the analyte serum levels are measured using achromatography combined mass spectrometry method (e.g., LC-MS/MS orGC-MS).

In one aspect, the compositions and oral dosage forms can include apharmaceutically acceptable carrier comprising said carrier comprises atleast one of alpha-tocopherol, glyceryl monocaprylate, propylene glycolmonolaurate, PEG-35 castor oil, PEG-40 hydrogenated castor oil, and acombination thereof that provides formation of either3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or both in an amountsufficient to treat a CNS disorder when orally administered to asubject.

In one embodiment, pregn-4-ene-3,20-dione compositions and oral dosageforms can be formulated to provide therapeutically effective amounts of3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or both relative to apregn-4-ene-3,20-dione composition or method utilizing apurpose-inadequate carrier. In other words, to provide compositions thatare therapeutically effective for treating a CNS disorder when orallyadministered to a subject. In another aspect, the pregn-4-ene-3,20-dionecan be in a form that maximizes formation of 3α-OH-5α-pregnan-20-one,3α-OH-5β-pregnan-20-one, or both when orally administered to a subject.In another aspect, the pregn-4-ene-3,20-dione can be in a form that whenorally administered to a subject increases formation of either3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or both. In oneaspect, the present compositions and methods, provide increasedformation of 3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or bothwhen orally administered to a subject, as compared to an equivalentamount of pregn-4-ene-3,20-dione administered from a composition ormethod that is purpose-inadequate. In another aspect, the presentcompositions and methods of provide increased formation of3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or both when orallyadministered to a subject as compared to an equivalent amount of amicronized administration administered to said subject. In some aspects,the micronized pregn-4-ene-3,20-dione can be administered in an oil oroil-based carrier.

In one embodiment, the composition can be formulated as an oral dosageform that has from about 10 mg to about 400 mg ofpregn-4-ene-3,20-dione. In one aspect, the oral dosage form can be aliquid, a semi-liquid, a semi solid, a sprinkle, an emulsion, adispersion, a granule, a syrup, a suspension, a capsule, a tablet, achew, or a drink.

In yet another embodiment, dosage regimens and methods of treating a CNSdepression disorder in a subject are provided and can include orallyadministering a composition comprising a therapeutically effectiveamount of pregn-4-ene-3,20-dione to the subject. In one aspect, thetherapeutically effective amount of pregn-4-ene-3,20-dione can providean amount (e.g. average serum levels, C_(avg) or peak serum levels,C_(max)) of 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or boththat is sufficient to treat the CNS disorder. In another aspect, thetherapeutically effective amount of pregn-4-ene-3,20-dione in acomposition can be in a form that provides a therapeutically effectiveamount of 3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or both fortreating the CNS disorder in the subject. In yet another aspect, thepregn-4-ene-3,20-dione can be combined with a carrier that is sufficientto provide a therapeutically effective amount of3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or both for treatingthe CNS disorder in the subject.

In yet another embodiment, dosage regimens and methods of treating a CNSdepression disorder in a female comprising a pregnant female or a femalewho has given birth within at least one of one month, six months, andtwelve months.

Compositions

As previously discussed, reported serum levels of neurosteroidmetabolites after oral administration of compositions with predominantlycrystalline pregn-4-ene-3,20-dione or sub-therapeutic doses do notresult in adequate levels to effectively treat CNS depression disorders.In addition, oral pregn-4-ene-3,20-dione as a prodrug has resulted inerratic neurosteroid levels and inconsistent pharmacodynamic effectstherefore, an enhanced way of treating CNS depression disorders would beuseful.

In one embodiment, an oral pharmaceutical composition can include atherapeutically effective amount of pregn-4-ene-3,20-dione and apharmaceutically acceptable carrier that provides formation of3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or both in an amountsufficient to treat a CNS depression disorder when orally administeredto a subject. In some aspects, the carrier can maximize, speed, orotherwise impact formation of 3α-OH-5α-pregnan-20-one,3α-OH-5β-pregnan-20-one, or both from the pregn-4-ene-3,20-dionecomposition when administered to a subject. In some aspects, the carriercan impact release of the pregn-4-ene-3,20-dione when administered to asubject. In some aspects, the carrier can impact generation of the3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or both whenadministered to a subject. In some aspects, the carrier can impactgeneration of 3β-OH-5α-pregnan-20-one, 3β-OH-5β-pregnan-20-one, or bothwhen administered to a subject.

In some aspects, the pregn-4-ene-3,20-dione form can impact thegeneration of 3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or bothwhen administered to a subject. In some aspects, thepregn-4-ene-3,20-dione form can impact generation of3β-OH-5α-pregnan-20-one, 3β-OH-5β-pregnan-20-one, or both whenadministered to a subject.

In some aspects, the pregn-4-ene-3,20-dione daily dose or dosing regimencan impact generation of 3α-OH-5α-pregnan-20-one,3α-OH-5β-pregnan-20-one, or both when administered to a subject. In someaspects, the pregn-4-ene-3,20-dione daily dose or dosing regimen canimpact generation of 3β-OH-5α-pregnan-20-one, 3β-OH-5β-pregnan-20-one,or both when administered to a subject.

In another aspect, the pregn-4-ene-3,20-dione can be in a form that whenorally administered to a subject maximizes, speeds, or otherwise impactsincreases formation of 3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one,or both. In one embodiment, the pregn-4-ene-3,20-dione can be in a formthat increases formation of 3α-OH-5α-pregnan-20-one,3α-OH-5β-pregnan-20-one, or both as compared to an equivalent amount ofa micronized administration. For example, the formation of3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or both can beincreased by up to about 8 times or 800% when compared to an equivalentamount of a micronized administration.

The therapeutically effective amount of pregn-4-ene-3,20-dione can vary.In one example, the therapeutically effective amount ofpregn-4-ene-3,20-dione can be present in the composition or oral dosageform an amount greater than one or more of: 0.0001 wt %, 0.001 wt %,0.01 wt %, 0.1 wt %, 0.5 wt %, 1.0 wt %, 2.0 wt %, 5.0 wt %, 10.0 wt %,15.0 wt %, 20.0 wt %, or combinations thereof. In another example, thetherapeutically effective amount of pregn-4-ene-3,20-dione can bepresent in an amount of from about 0.0001 wt % to about 10 wt % of thecomposition or oral dosage form. In another example, the therapeuticallyeffective amount of pregn-4-ene-3,20-dione can be present in an amountof from about 10.0001 wt % to about 20 wt %. In yet another example, thetherapeutically effective amount of pregn-4-ene-3,20-dione can bepresent in an amount of from about 20.001 wt % to about 24.999 wt %. Inanother example, the therapeutically effective amount ofpregn-4-ene-3,20-dione can be present in an amount of from 0.06 wt % toabout 25 wt % or 3 wt % to 10 wt %.

In one aspect, the present compositions and methods comprise at leastone of a substantially non-crystalline and/or a substantiallysolubilized pregn-4-ene-3,20-dione form.

The therapeutically effective amount of pregn-4-ene-3,20-dione can becombined with a pharmaceutically acceptable carrier to form3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one, or both in an amountsufficient to treat a CNS depression disorder when administered to asubject. In some embodiments, such a carrier can include an additive. Awide variety of additives can be used to fully or partially solubilizepregn-4-ene-3,20-dione in the pharmaceutical composition in order toprovide therapeutically effective levels of 3α-OH-5α-pregnan-20-one and3α-OH-5β-pregnan-20-one for treating a CNS disorder (e.g., post-partumdepression). Examples of suitable additives can include: (i) tocopherol(e.g. vitamin E) or its derivatives; (ii) fatty acids or their salts;(iii) glyceryl fatty acid esters; (iv) PEG glycerides of fatty acidesters; (v) polyglycerol fatty acid esters; (vi) triglycerides; (vii)hydrogenated polyoxyl vegetable oils or glycerides; (viii) propyleneglycol fatty acid esters; (ix) edible oils; (x) sterols or itsderivatives, (xi) omega oils, such as omega fatty acids, fish oil, flaxseed oil, algae oil, and the like, or combinations thereof.

In one aspect, vitamin E or its derivatives can comprise:alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol,tocopherol acetate, tocopherol linoleate, tocopherol succinate,tocotrienols (alpha-, beta-, gamma-, or delta-), tocofersolan or TPGS(PEG derivatives of alpha-tocopherol), the like, or combinationsthereof.

In another aspect, fatty acids or their salts can comprise: octanoicacid, capric acid, lauric acid, myristic acid, palmitic acid, stearicacid, oleic acid, linoleic acid, linoelaidic acid, sodium caproate,sodium caprylate, sodium laurate, sodium myristate, sodium palmitate,sodium oleate, sodium stearate, SLS, sodium lauryl sarcosinate, sodiumdioctyl sulfosuccinate, sodium cholate, sodium taurocholate, the like,or combinations thereof.

In another aspect, glyceryl fatty acid esters can comprise: glycerylmonooleate, glyceryl monoleate/linoleate, glyceryl monolinoleate,glyceryl ricinoloeate, glyceryl monolaurate, glyceryl monopalmitate,glyceryl monostearate, glyceryl mono-/di-oleate, glycerylpalmitate/stearate, glyceryl acetate, glyceryl laurate, glycerylcitrate/lactate/oleate/linoleate, glyceryl caprylate, glycerylcaprylate/caprate, glyceryl dicaprylate/dicaprate, mono-/di-acetylatedmonoglycerides, glyceryl monostearate, glyceryl dilaurate, glyceryldioleate, the like, or combinations thereof.

In yet another aspect, PEG glycerides of fatty acid esters can comprise:PEG fatty acid monoesters, PEG glycerol fatty acid esters, PEG fattyacid diesters, PEG fatty acid mono-/di-ester mixtures, PEG triglyceridesof fatty acid esters, the like, or combinations thereof. PEG glycerolfatty acid esters can comprise: PEG glyceryl laurate, PEG glyceryllaurate, PEG glyceryl caprylate, PEG glyceryl caprate, PEG glyceryloleate, PEG glyceryl mono-/di-fatty acid ester mixtures, the like, orcombinations thereof. PEG fatty acid monoesters can comprise: esters ofcaprylic acid, capric acid, lauric acid, oleic acid, and stearic acid,the like, or combinations thereof. Examples of the PEG fatty acidmonoesters can include PEG (1-100, 200, 300, 400) monocaprylate, PEG(1-100, 200, 300, 400) monocaprate, PEG (1-100, 200, 300, 400)monolaurate, PEG (1-100, 200, 300, 400) monooleate, PEG (1-100, 200,300, 400) monopalmitate, PEG (1-100, 200, 300, 400) monostearate, andPEG (1-100, 200, 300, 400) monococoate, the like, or combinationsthereof. PEG fatty acid diesters can comprise PEG (4-32) dicaprylate,PEG (4-32) dicaprate, PEG (4-32) dilaurate, PEG (4-32) dioleate, PEG(4-32) distearate, and PEG (4-32) dipalmitate, the like, or combinationsthereof. PEG fatty acid mono-/di-ester mixtures can comprise: PEGcaprylate/caprate, PEG mono-/di-caprylate, PEG mono-/di-caprate, PEGmono-/di-laurate, PEG mono-/di-oleate, and PEG mono-/di-stearate thelike, or combinations thereof. PEG triglycerides of fatty acid esterscan comprise: lauroyl polyoxylglycerides, stearoyl polyoxylglycerides,oleoyl polyoxyl glycerides, linoleoyl polyoxyl glycerides, lauroylpolyoxyl glycerides, caprylocaproyl polyoxyl glycerides, and behenoylpolyoxylglycerides the like, or combinations thereof.

In a further aspect, polyglycerol fatty acid esters can comprise:polyglyceryl (2, 3, 4, 6, 10) oleate, polyglyceryl (2, 3, 4, 6, 10)dioleate, polyglyceryl (2, 3, 4, 6, 10) trioleate, polyglyceryl (2, 3,4, 6, 10) laurate, polyglyceryl (2, 3, 4, 6, 10) dilaurate, polyglyceryl(2, 3, 4, 6, 10) trilaurate, polyglyceryl (2, 3, 4, 6, 10) stearate,polyglyceryl (2, 3, 4, 6, 10) distearate, polyglyceryl (2, 3, 4, 6, 10)tristearate, polyglyceryl (2, 3, 4, 6, 10) mono-/di-oleate, polyglyceryl(3,6,10) caprate, polyglyceryl (3,6,10) dicaprate, polyglyceryl (3,6,10)tricaprate, polyglyceryl (3,6,10) caprylate, polyglyceryl (3,6,10)dicaprylate, polyglyceryl (3,6,10) tricaprylate, polyglyceryl (3,6,10)polystearate, polyglyceryl (3,6,10) polyoleate, polyglyceryl (3,6,10)mono-/di-oleate, polyglyceryl (3,6,10) caprylate, polyglyceryl (3,6,10)polycaprylate, polyglyceryl (3,6,10) caprate, polyglyceryl (3,6,10)polycaprate, and polyglyceryl (3,6,10) caprylate/caprate, the like, orcombinations thereof.

In another aspect, triglycerides can comprise: glyceryl tricaprylate,glyceryl tricaprate, glyceryl tricaprylate/tricaprate, glyceryltricaprylate/tricaprate/trisuccinate, glyceryl trioleate, glyceryltristearate, glyceryl trilaurate, medium chain natural oils, the like,or combinations thereof.

In yet another aspect, hydrogenated polyoxyl vegetable oils orglycerides can comprise: castor oil or hydrogenated castor oil, or anedible vegetable oil such as corn oil, olive oil, peanut oil, palmkernel oil, apricot kernel oil, peppermint oil, coconut oil, sunflowerseed oil, or almond oil, the like, or combinations thereof. The polyoxylgroup can include glycerol, propylene glycol, ethylene glycol,polyethylene glycol, sorbitol, pentaerythritol, the like, orcombinations thereof. Examples of hydrogenated polyoxyl vegetable oilsor glycerides can comprise: PEG-35 castor oil (Incrocas-35, KolliphorEL, Cremophor EL), PEG-40 hydrogenated castor oil (Kolliphor RH 40,Cremophor RH40), PEG-25 trioleate (TAGATRTO), PEG-60 corn glycerides(Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel oil(Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenatedcastor oil (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labrasol),PEG-6 caprylic/capric glycerides (Softigen 767), PEG-5 hydrogenatedcastor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castoroil, PEG-6 corn oil (Labrafil M. 2125 CS), PEG-6 almond oil (Labrafil M1966 CS), PEG-6 apricot kernel oil (Labrafil M 1944CS), PEG-6 olive oil(Labrafil M 1980 CS), PEG-6 peanut oil (Labrafil M 1969 CS), PEG-6hydrogenated palm kernel oil (Labrafil M2130 BS), PEG-6 palm kernel oil(Labrafil M 2130 CS), PEG-6 triolein (Labrafil M 2735 CS), PEG-8 cornoil (Labrafil WL 2609 BS), PEG-20 corn glycerides (Crovol M40), andPEG-20 almond glycerides (Crovol A40), the like, or combinationsthereof.

In one aspect, propylene glycol fatty acid esters can comprise:propylene glycol monolaurate (Lauroglycol FCC), propylene glycolricinoleate (Propymuls), propylene glycol monooleate (Myverol P-06),propylene glycol dicaprylate/dicaprate (Captex 200), and propyleneglycol dioctanoate (Captex 800), propylene glycol monocaprylate (Capryol90, Nikkol Sefsol 218), propylene glycol myristate, propylene glycolmonostearate, propylene glycol ricinolate, propylene glycol isostearate,propylene glycol caprylate/caprate, propylene glycol dioleate, propyleneglycol distearate, propylene glycol dilaurate, propylene glycoldicaprylate, and propylene glycol dicaprate, the like, or combinationsthereof.

In another aspect, edible oils can comprise: corn oil, olive oil, peanutoil, coconut oil, peppermint oil, sunflower seed oil, castor oil,safflower oil, borage oil, cottonseed oil, soybean oil, palm kernel oil,apricot kernel oil, almond oil, omega-3 oil or its derivatives, thelike, or combinations thereof.

In one aspect, sterols or its derivatives can comprise: cholesterol,sitosterol, lanosterol, phytosterol, its PEG derivatives, the like, orcombinations thereof.

In one embodiment, an additive can be a substance that can be added tothe pharmaceutical formulation to enhance the solubilization,separation, or dispersion of the particles, or to enhance thedissolution and further absorption of the particles into the body.Examples of additives can include a lipophilic additive when it has anHLB value of 10 or less, or a hydrophilic additive when it has an HLBvalue of greater than 10.

In one aspect, the pharmaceutically acceptable carrier can comprise ahydrophilic additive, a lipophilic additive, or a combination thereof.

In one aspect, lipophilic additives can comprise: mono-, di-glyceridesof fatty acids, reaction mixtures of alcohols or polyalcohols with avariety of natural and/or hydrogenated oils such as PEG-5 hydrogenatedcastor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castoroil, PEG-6 corn oil (e.g. Labrafil M 2125 CS), PEG-6 almond oil (e.g.Labrafil M 1966 CS), PEG-6 apricot kernel oil (e.g. Labrafil M 1944 CS),PEG-6 olive oil (e.g. Labrafil M 1980 CS), PEG-6 peanut oil (e.g.Labrafil M 1969 CS), PEG-6 hydrogenated palm kernel oil (e.g. Labrafil M2130 BS), PEG-6 palm kernel oil (e.g. Labrafil M 2130 CS), PEG-6triolein (e.g. Labrafil M 2735 CS), PEG-8 corn oil (e.g. Labrafil WL2609 BS), PEG-20 corn glycerides (e.g. Crovol M40), PEG-20 almondglycerides (e.g. Crovol A40), lipophilicpolyoxyethylene-polyoxypropylene block co-polymers (e.g. Pluronic L92,L101, L121 etc.), propylene glycol fatty acid esters, such as propyleneglycol monolaurate (e.g. Lauroglycol FCC), propylene glycol ricinoleate(e.g. Propymuls), propylene glycol monooleate (e.g. Myverol P-06),propylene glycol dicaprylate/dicaprate (e.g. CAPTEX® 200), and propyleneglycol dioctanoate (e.g. CAPTEX® 800), propylene glycol mono-caprylate(e.g. CAPRYOL® 90); propylene glycol oleate (e.g. Lutrol OP2000);propylene glycol myristate; propylene glycol mono stearate; propyleneglycol hydroxy stearate; propylene glycol ricinoleate; propylene glycolisostearate; propylene glycol mono-oleate; propylene glycoldicaprylate/dicaprate; propylene glycol dioctanoate; propylene glycolcaprylate-caprate; propylene glycol dilaurate; propylene glycoldistearate; propylene glycol dicaprylate; propylene glycol dicaprate;mixtures of propylene glycol esters and glycerol esters such as mixturescomposed of the oleic acid esters of propylene glycol and glycerol (e.g.ARLACEL® 186); sterol and sterol derivatives such as cholesterol,sitosterol, phytosterol, phytosterol fatty acid esters, PEG-5 soyasterol, PEG-10 soya sterol, PEG-20 soya sterol, and the like; glycerylpalmitostearate, glyceryl stearate, glyceryl distearate, glycerylmonostearate, or a combination thereof; sorbitan fatty acid esters suchas sorbitan monolaurate (e.g. Arlacel 20), sorbitan monopalmitate (e.g.Span-40), sorbitan monooleate (e.g. Span-80), sorbitan monostearate, andsorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monooleate, Linoleoyl Polyoxyl-6 glycerides, polyglyceryl3-oleate, lauroyl PEG-32 glycerides, sorbitan trioleate, sorbitansesquioleate, sorbitan tristearate, sorbitan monoisostearate, sorbitansesquistearate, and the like; fatty acids such as capric acid, caprylicacid, oleic acid, linoleic acid, myristic acid, menthol, mentholderivatives, lecithin, phosphatidyl choline, bile salts, and the like,and mixtures thereof. In some cases, an additive for the compositionsand oral dosage forms can be a lipophilic surfactant.

The pharmaceutically acceptable carrier can also comprise a hydrophilicadditive. In one aspect, the hydrophilic additive can comprise withoutlimitation, non-ionic surfactants, ionic surfactants, zwitterionicsurfactants, the like, or combinations thereof. Suitable hydrophilicsurfactants can include: alcohol-oil transesterification products;polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetableoils; alkyl sulphate salts, dioctyl sulfosuccinate salts; polyethyleneglycol fatty acids esters; polyethylene glycol fatty acids mono- anddi-ester mixtures; polysorbates, polyethylene glycol derivatives oftocopherol, the like, or combinations thereof. Two or more hydrophilicadditives from the same or different classes can be referred to as thehydrophilic surfactant unless explicitly specified. In one aspect,non-limiting examples of hydrophilic surfactants can comprise PEG-8caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoylmacrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor oil,SLS, sodium dioctyl sulfosuccinate, polyethylene glycol fatty acidsmono- and di-ester mixtures, polysorbate 80, polysorbate 20,polyethylene glycol 1000 tocopherol succinate, phytosterols, phytosterolfatty acid esters, the like, or combinations thereof. In some cases, ahydrophilic additive for the compositions and oral dosage forms can be ahydrophilic surfactant.

In yet another aspect, additives can comprise sterols and derivatives ofsterols. In various aspects, these additional agents can be hydrophilicor lipophilic. Examples of hydrophilic sterols include: lanosterolPEG-24 cholesterol ether (e.g. Solulan C-24, Amerchol), PEG-30 soyasterol (e.g. Nikkol BPS-30, from Nikko), PEG-25 phyto sterol (e.g.Nikkol BPSH-25 from Nikko), PEG-30 cholestanol (e.g. Nikkol DHC, fromNikko). Examples of Lipophilic Sterol Surfactants are Cholesterol,sitosterol, Phytosterol (e.g. GENEROL series from Henkel), PEG-5 soyasterol (e.g. Nikkol BPS-S, from Nikko), PEG-10 soya sterol (e.g. NikkolBPS-10 from Nikko), PEG-20 soya sterol (e.g. Nikkol BPS-20 from Nikko),the like, or combinations thereof.

In another aspect, the oral compositions can further comprise apolymeric release modifier. The polymeric release modifier can comprise:celluloses, such as hydroxypropyl celluloses low molecular weight, lowviscosity types (e.g. Methocel E5, E6, E10 E15, LV100 etc. grades),hydroxypropyl celluloses having higher molecular weight, medium to highviscosity (e.g. Methocel K4M, K15M, K100M etc.), polyvinylpyrrolidones(e.g. Kollidon k17, K30 etc.), polyvinyl acetates, hydroxypropylmethylcellulose (HPMC), hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP) and crosslinked PVP polyvinyl alcohol(PVA), PVA/PVP copolymers and PVA/PVP copolymers with hydrophobicmonomers such as methyl methacrylate, vinyl acetate, and the like,hydrophilic polyurethanes containing large PEO blocks, Sodiumcroscarmellose, carrageenan, hydroxyethyl cellulose (HEC), carboxymethylcellulose (CMC) and carboxy ethyl cellulose (CEC), sodium alginate,polycarbophil, gelatin, Xanthan gum, and sodium starch glycolate, thelike, or combinations thereof.

The pharmaceutically acceptable carrier can be combined with orotherwise include additives in various amount ranges. For example, thelipophilic additive and hydrophilic additive can be present in amountssuch that the ratio of amount (wt %) of lipophilic additive to amount(wt %) of hydrophilic additive is greater than 2:1. In another aspect,the lipophilic additive and hydrophilic additive can be present inamounts such that the ratio of amount (wt %) of lipophilic additive toamount (wt %) of hydrophilic additive is greater than 2.5:1. In anotheraspect, the lipophilic additive and hydrophilic additive can be presentin amounts such that the ratio of amount (wt %) of lipophilic additiveto amount (wt %) of hydrophilic additive is greater than 3.5:1. In stillanother aspect, the lipophilic additive and hydrophilic additive can bepresent in amounts such that the ratio of amount (wt %) of lipophilicadditive to amount (wt %) of hydrophilic additive is at least 6.5:1.

In certain examples, the hydrophilic additive can make up about 1% w/wto about 80% w/w, about 5% w/w to about 70% w/w, about 10% w/w to about60% w/w, about 15% w/w to about 55% w/w, about 20% w/w to about 50% w/w,about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50%w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about75% w/w, or about 80% w/w of any pharmaceutical composition describedherein. In some examples, the lipophilic additive can make up about 1%w/w to about 90% w/w, about 5% w/w to about 80% w/w, about 5% w/w toabout 70% w/w, about 10% w/w to about 60% w/w, about 1% w/w to about 50%w/w, about 5% w/w to about 45% w/w, about 10% w/w to about 40% w/w,about 15% w/w to about 35% w/w, about 20% w/w to about 30% w/w, about 5%w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 10% w/w, about 15%w/w, about 20% w/w, about 25% w/w, or greater than about 30% w/w of anypharmaceutical composition described herein.

Co-solvents can partially solubilize Pregn-4-ene-3,20-dione whenpresented in an effective amount. Examples of suitable co-solvents cancomprise without limitation: alcohols and polyols, such as ethanol,propanol, isopropanol, butanol, benzyl alcohol, ethylene glycol,propylene glycol, butanediols, glycerin or its derivatives thereof,glycerol, diglycerol, polyglycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, triacetin, trimethyl citrate,polyethylene glycol, polypropylene glycol, polyvinylalcohol,hydroxypropyl methylcellulose and other cellulose derivatives,cyclodextrins or its derivatives, the like, or combinations thereof.

In one embodiment, the present oral compositions or dosage forms canprovide a ratio of pregn-4-ene-3,20-dione to alpha-tocopherol from about0.3 to 2.0, such as about 0.3, about 0.4, about 0.5, about 0.6, about0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3,about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, andabout 2.0.

In another embodiment, the present oral compositions or dosage forms canprovide a ratio of pregn-4-ene-3,20-dione to glyceryl monocaprylate lessthan about 0.2, such as about 0.2, about 0.19, about 0.18, about 0.17,about 0.16, about 0.15, about 0.14, about 0.13, about 0.12, about 0.11,about 0.10, about 0.09, and less than about 0.09.

In a further embodiment, the present oral compositions or dosage formscan provide a ratio of alpha-tocopherol to a hydrophilic ingredient fromabout 0.05 to 4.0, such as about 0.05, about 0.1, about 0.3, about 0.5,about 0.7, about 0.9, about 1.1, about 1.3, about 1.4, about 1.7, about2.0, about 2.3, about 2.6, about 2.9, about 3.2, about 3.5, and about4.0.

In yet another embodiment, the present oral compositions or dosage formscan provide a ratio of glyceryl monocaprylate to a hydrophilicingredient from about 1 to 20 and about 1 to 10, such as about 1, about2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, andabout 10. In another example, the ratio of glyceryl monocaprylate to ahydrophilic ingredient can be from less than about 2, about 1.9, about1.8, about 1.7, about 1.6, about 1.5, about 1.4, about 1.3, about 1.2,about 1.1, and about 1.0.

In one aspect, the composition can be formulated as a solution, anemulsion, a liquid, a semi-liquid, a suspension, a semi solid, asprinkle, an emulsion, a dispersion, a granule, a syrup, a suspension, acapsule, a tablet, a chew, or a drink, or the like, or combinationsthereof. In one example, the composition can form a dispersion, anemulsion, a solution, or a micellar solution upon 10× or 100× dilutionwith an aqueous bile salt comprising simulated gastric or intestinalmedia or water (e.g. FeSSIF, or FaSSIF media well known in the art). Inanother example, the composition can remain substantially solubilizedupon 10× or 100× dilution with an aqueous bile salt comprising simulatedgastric or intestinal media or water. In another example, thecomposition can form a dispersion upon 10× or 100× dilution with anaqueous bile salt comprising simulated gastric or intestinal media orwater with a mean dispersion particle size of less than 300 nm or a UVabsorbance of less than 3 units when measured at 400 nm.

In one embodiment, the pregn-4-ene-3,20-dione can include a crystallineform that is milled, nanosized, micronized, ultra-micronized, the like,or combinations thereof. In one aspect, the present composition consistsof only pregn-4-ene-3,20-dione active in the carrier. In another aspect,the present composition consists of and is free of estradiol. In oneanother aspect, a specified weight percentage of thepregn-4-ene-3,20-dione in the carrier can be in a non-crystalline form(e.g., amorphous solid, a solution an emulsion, a liquid, a semi-liquid,a suspension, or the like). In one example, at least about 50% of thepregn-4-ene-3,20-dione in the carrier can be in a non-crystalline state.In another example, at least about 65% of the pregn-4-ene-3,20-dione inthe carrier can be in a non-crystalline state. In yet another example,at least about 80% of the pregn-4-ene-3,20-dione in the carrier can bein a non-crystalline state. In another example, at least about 95% ofthe pregn-4-ene-3,20-dione in the carrier can be in a non-crystallinestate. In one aspect, the present oral compositions can be comprisedsubstantially free of micronized suspension form of crystallinepregn-4-ene-3,20-dione.

In one embodiment, oral compositions herein can be free of orsubstantially free of solid forms of pregn-4-ene-3,20-dione. In anotherembodiment, the present oral compositions can be free of orsubstantially free of release modulators.

In another aspect, a specified weight percentage of thepregn-4-ene-3,20-dione in the carrier can be solubilized. In oneexample, from about 50% to about 100% of the pregn-4-ene-3,20-dione inthe carrier can be solubilized. In another example, from about 50% toabout 65% of the pregn-4-ene-3,20-dione in the carrier can besolubilized. In yet another example, from about 65% to about 85% of thepregn-4-ene-3,20-dione in the carrier can be solubilized. In anotherexample, from about 85% to about 100% of the pregn-4-ene-3,20-dione inthe carrier can be solubilized.

FIG. 2 shows a plot of the release of several examples of the presentoral compositions comprising pregn-4-ene-3,20-dione and a compositioncomprising a micronized pregn-4-ene-3,20-dione suspension in oilperformed using a USP Type I dissolution apparatus in 900 mL ofdeionized water with 2.0% (w/v) of SLS at 100 rpm at 37° C.

In one example, as shown in FIG. 2, the present compositions can releasegreater than about 50% of the pregn-4-ene-3,20-dione after 15 minuteswhen measured using a USP Type I dissolution apparatus in 900 mL ofdeionized water with 2.0% (w/v) of SLS at 100 rpm at 37° C.

In another example, as shown in FIG. 2, the present compositions canrelease greater than about 75% of the pregn-4-ene-3,20-dione after 30minutes when measured using a USP Type I dissolution apparatus in 900 mLof deionized water with 2.0% (w/v) of SLS at 100 rpm at 37° C.

In another example, as shown in FIG. 2, the present compositions canrelease greater than about 90% of the pregn-4-ene-3,20-dione after 60minutes when measured using a USP Type I dissolution apparatus in 900 mLof deionized water with 2.0% (w/v) of SLS at 100 rpm at 37° C.

In another example, as shown in FIG. 2, the present compositions canrelease greater than 50% of the pregn-4-ene-3,20-dione in 4 hours fromthe when measured using a USP Type I dissolution apparatus in 900 mL ofdeionized water with 2.0% (w/v) of SLS at 100 rpm at 37° C.

In another example, as shown in FIG. 2, the present can release greaterthan about 30% more of pregn-4-ene-3,20-dione after 15 minutes ascompared to the % release from a micronized administration.

FIG. 3 shows a plot of the release of several examples for oralcompositions comprising pregn-4-ene-3,20-dione performed using a USPType II dissolution apparatus in 900 mL of deionized water with 0.25%(w/v) of SLS at 75 rpm at 37° C.

In one example, as shown in FIG. 3, the present compositions can releasegreater than about 50% of the pregn-4-ene-3,20-dione after 20 minuteswhen measured using a USP Type II dissolution apparatus in 900 mL ofdeionized water with 0.25% (w/v) of SLS at 75 rpm at 37° C.

In another example, as shown in FIG. 3, the present compositions canrelease greater than about 75% of the pregn-4-ene-3,20-dione after 30minutes when measured using a USP Type II dissolution apparatus in 900mL of deionized water with 0.25% (w/v) of SLS at 75 rpm at 37° C.

In another example, as shown in FIG. 3, the present compositions canrelease greater than about 90% of the pregn-4-ene-3,20-dione after 60minutes when measured using a USP Type II dissolution apparatus in 900mL of deionized water with 0.25% (w/v) of SLS at 75 rpm at 37° C.

In another example, as shown in FIG. 3, the present compositions canrelease greater than 50% of the pregn-4-ene-3,20-dione in 4 hours fromthe when measured using a USP Type II dissolution apparatus in 900 mL ofdeionized water with 0.25% (w/v) of SLS at 75 rpm at 37° C.

In yet another example, the present compositions can release greaterthan about 30% more of the pregn-4-ene-3,20-dione after 20 minutes ascompared to a substantially equivalent amount of a micronizedadministration when measured using a USP Type III reciprocating cylinderdissolution apparatus at 30 dips per minute in 250 mL of a solution of0.1N HCl with 3% SLS at 37° C.

In another embodiment, an oral pharmaceutical composition or oral dosageform can include an amount of pregn-4-ene-3,20-dione, that providesGABA_(A) receptor binding pregn-4-ene-3,20-dione metabolites in amountsthat therapeutically effect CNS disorders when administered to asubject. For example, in one embodiment, the composition or oral dosageform can include a pharmaceutically acceptable carrier that maximizes orotherwise accelerates formation of GABA_(A) receptor PAMs whenadministered to a subject. In yet another embodiment, the composition ororal dosage form can include pregn-4-ene-3,20-dione in a form thatmaximizes or otherwise speeds or accelerates formation of GABA_(A)receptor PAMs when administered to a subject. In yet another embodiment,the composition or oral dosage formulation can include a therapeuticallyeffective amount of pregn-4-ene-3,20-dione that increases GABA_(A)receptor PAMs formation as compared to an equivalent amount of amicronized administration. In one aspect, the increased metaboliteformation for the composition can be up to about 8 times when comparedto an equivalent amount of a micronized administration. In one aspect,GABA_(A) receptor PAMs can be selected from the group comprising:3α-OH-5α-pregnan-20-one and 3α-OH-5β-pregnan-20-one.

In one embodiment, the composition or oral dosage form can include apharmaceutically acceptable carrier that minimizes formation of GABA_(A)receptor NAMs when administered to a subject. In yet another embodiment,the composition or oral dosage form can include pregn-4-ene-3,20-dionein a form that minimizes or otherwise decrease formation of GABA_(A)receptor NAMs when administered to a subject. In yet another embodiment,the composition or oral dosage formulation can include a therapeuticallyeffective amount of pregn-4-ene-3,20-dione that increases GABA_(A)receptor NAMs formation as compared to an equivalent amount a micronizedadministration administered the subject. In one aspect, GABA_(A)receptor NAMs can be selected from the group comprising:3β-OH-5α-pregnan-20-one and 3β-OH-5β-pregnan-20-one.

Dosage Forms and Dosing Regimens

In one embodiment, the composition can be formulated as an oral dosageform. The oral dosage form can be a member selected from the groupconsisting of: a liquid, a semi-liquid, a semi solid, a sprinkle, anemulsion, a dispersion, a granule, a syrup, a suspension, a capsule, atablet, a chew, or a drink the like, or combinations thereof In oneaspect, the composition can be formulated as an oral dosage form thathas from about 10 mg to about 200 mg of pregn-4-ene-3,20-dione. Inanother aspect, the composition can be formulated as an oral dosage formthat has from about 10 mg to about 400 mg of pregn-4-ene-3,20-dione thatwhen orally administered to a subject provides a 3α-OH-5α-pregnan-20-oneC_(max) of greater than about 18 ng/ml, or a 3α-OH-5β-pregnan-20-oneC_(max) greater than about 11 ng/ml, a 3β-OH-5α-pregnan-20-one C_(max)of greater than about 2.5 ng/ml, or a 3β-OH-5β-pregnan-20-one C_(max)greater than about 2.0 ng/ml, or a combination thereof.

In a further embodiment, the present drink compositions or dosage formsmay be formulated as an oral dosage form comprising from about 10 mg toabout 900 mg of pregn-4-ene-3,20-dione in a unit dose drinks of about 15mL up to 90 mL. In one aspect, the present drink compositions or dosageforms can comprise from about 20 mg to about 750 mg ofpregn-4-ene-3,20-dione in a single unit dose drink. In one aspect, thepresent drink compositions or dosage forms can comprise from about 30 mgto about 600 mg of pregn-4-ene-3,20-dione in a single unit dose drink.In a further aspect, the present drink compositions or dosage forms cancomprise at least one of about 10 mg, about 20 mg, about 30 mg, about 40mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg,about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg,about 900 mg, or any amount between the above values ofpregn-4-ene-3,20-dione in a single unit dose drink.

In a further embodiment, the present drink compositions or dosage formscan comprise from pregn-4-ene-3,20-dione of about 0.06 w/w % to about1.0 w/w % in a single unit dose drink of about 15 mL to about 90 mL. Inan aspect, pregn-4-ene-3,20-dione comprised in the present drinkcompositions or dosage forms can be one of about 0.06 w/w %, about 0.07w/w %, about 0.08 w/w %, about 0.09 w/w %, about 0.1 w/w %, about 0.2w/w %, about 0.3 w/w %, about 0.4 w/w %, about 0.5 w/w %, about 0.6 w/w%, about 0.7 w/w %, about 0.8 w/w %, about 0.9 w/w %, or about 1.0 w/w %in a single unit dose drink of about 15 mL up to 90 mL.

In yet another embodiment, the present drink compositions or dosageforms can optionally comprise other carrier ingredients comprising atleast one of flavoring agents, sweeteners, antimicrobial preservatives,antioxidants, and edible fat. In one aspect, flavoring agents can beselected from natural and/or artificial flavors of strawberry, fruitpunch, cherry, bubble gum or a combination thereof. In another aspect,sweeteners can be selected from sucralose, sucrose, maltose, acesulfamepotassium, or a combination thereof. In other aspect, antimicrobialpreservatives can be selected from sodium benzoate, benzoic acid, methylparaben, propyl paraben, or a combination thereof. In yet furtheraspect, antioxidants can be selected from disodium edetate, sodiumcitrate, citric acid, ascorbic acid, ascorbyl palmitate,alpha-tocopherol, BHA, BHT, or a combination thereof.

In yet another embodiment, the present drink compositions or dosageforms comprising pregn-4-ene-3,20-dione can include about 10 to about 15g of total fat or can be administered with a snack or meal of at least10 g of total fat.

In one embodiment, the present oral compositions can comprise at leastone of less than 195 mg of pregn-4-ene-3,20-dione, less than 95 mg ofpregn-4-ene-3,20-dione, less than 70 mg of pregn-4-ene-3,20-dione, lessthan 58 mg of pregn-4-ene-3,20-dione, less than 48 mg ofpregn-4-ene-3,20-dione, less than 30.0% w/w of pregn-4-ene-3,20-dione,less than 17.3% w/w of pregn-4-ene-3,20-dione, less than 13.3% w/w ofpregn-4-ene-3,20-dione, less than 9.8% w/w of pregn-4-ene-3,20-dione,less than 8.8% w/w of pregn-4-ene-3,20-dione, less than 8.4% w/w ofpregn-4-ene-3,20-dione, less than 7.8% w/w of pregn-4-ene-3,20-dione,less than 7.0% w/w of pregn-4-ene-3,20-dione, less than 6.8% w/w ofpregn-4-ene-3,20-dione, less than 5.8% w/w of pregn-4-ene-3,20-dione, orless than 3.9% w/w of pregn-4-ene-3,20-dione.

In one embodiment, the present oral compositions can comprise at leastone of from 62 mg to 98 mg of pregn-4-ene-3,20-dione, from 78 mg to 145mg of pregn-4-ene-3,20-dione, from 155 mg to 195 mg ofpregn-4-ene-3,20-dione, from 2.8% w/w to 9.8% w/w ofpregn-4-ene-3,20-dione, from 7.2% w/w to 8.3% w/w ofpregn-4-ene-3,20-dione, from 8.2% w/w to 9.8% w/w ofpregn-4-ene-3,20-dione, from 8.8% w/w to 13.0% w/w ofpregn-4-ene-3,20-dione, from 10.2% w/w to 14.8% w/w ofpregn-4-ene-3,20-dione, or from 8.7% w/w to 22.3% w/w ofpregn-4-ene-3,20-dione.

In one embodiment, the present oral compositions can comprise at leastone of greater than 52 mg of pregn-4-ene-3,20-dione, greater than 62 mgof pregn-4-ene-3,20-dione, greater than 75 mg of pregn-4-ene-3,20-dione,greater than 102 mg of pregn-4-ene-3,20-dione, greater than 205 mg ofpregn-4-ene-3,20-dione, greater than 4.3% w/w of pregn-4-ene-3,20-dione,greater than 4.7% w/w of pregn-4-ene-3,20-dione, greater than 6.2% ofpregn-4-ene-3,20-dione, greater than 7.2% w/w of pregn-4-ene-3,20-dione,greater than 7.5% of pregn-4-ene-3,20-dione, greater than 9.2% w/w ofpregn-4-ene-3,20-dione, greater than 10.2% w/w ofpregn-4-ene-3,20-dione, greater than 13.4% w/w ofpregn-4-ene-3,20-dione, greater than 15.2% w/w ofpregn-4-ene-3,20-dione, greater than 17.7% w/w ofpregn-4-ene-3,20-dione, or greater than 22.7% w/w ofpregn-4-ene-3,20-dione.

In one embodiment, the present oral compositions can comprise at leastone of free of alcohol, less than 2.8% w/w of alcohol, less than 5.8%w/w of alcohol, less than 9.8% w/w of alcohol, less than 15.2% w/w ofalcohol, from 3.2% w/w to 6.8% w/w of alcohol, greater than 6.2% w/w ofalcohol, greater than 7.2% w/w of alcohol, greater than 10.2% w/w ofalcohol, greater than 15.6% w/w of alcohol, and. free of ethanol.

In one embodiment, the present oral compositions can comprise at leastone of free of hydrophilic solidifying agents, free of PEG 8000, lessthan 5.9% w/w of PEG 8000, less than 6.0% w/w of PEG 8000, less than7.7% w/w of PEG 8000, greater than 6.1% w/w of PEG 8000, greater than6.4% w/w of PEG 8000, and greater than 8.0% w/w of PEG 8000.

In one embodiment, the present oral compositions can comprise at leastone of free of propylene glycol, less than 108 mg of propylene glycol,and greater than 183 mg of propylene glycol.

In one embodiment, the present oral compositions can comprise at leastone of free of triethyl citrate, less than 5.8% w/w of triethyl citrate,and greater than 6.2% w/w of triethyl citrate.

In one embodiment, the present oral compositions can comprise at leastone of free of triacetin, less than 5.8% w/w of triacetin, and greaterthan 6.2% w/w of triacetin.

In one embodiment, the present oral compositions can comprise at leastone of free of lecithin or its derivatives, less than 1.5% w/w oflecithin, greater than 0.4% w/w of lecithin, and greater than 1.7% w/wof lecithin.

In one embodiment, the present oral compositions can comprise at leastone of free of lauroyl polyoxyl-32 glycerides, less than about 1.2% w/wof lauroyl polyoxyl-32 glycerides, less than about 2.8% w/w of lauroylpolyoxyl-32 glycerides, less than about 9.5% w/w of lauroyl polyoxyl-32glycerides, from about 1.8% w/w to 19.0% w/w of lauroyl polyoxyl-32glycerides, from about 3.2% w/w to about 5.8% w/w of lauroyl polyoxyl-32glycerides, greater than about 1.8% w/w of lauroyl polyoxyl-32glycerides, greater than about 6.2% w/w of lauroyl polyoxyl-32glycerides, greater than about 9.5% w/w of lauroyl polyoxyl-32glycerides, greater than about 10.5% w/w of lauroyl polyoxyl-32glycerides, and greater than about 19.8% w/w of lauroyl polyoxyl-32glycerides.

In one embodiment, the present oral compositions can comprise at leastone of free of polysorbate, less than 4.5% w/w of polysorbate, from 5.0%w/w to 6.8% w/w of polysorbate, greater than 4.7% w/w of polysorbategreater than 7.7% w/w of polysorbate, and free of polysorbate 80,

In one embodiment, the present oral compositions can comprise at leastone of free of hydrophilic surfactants, greater than 1.1% w/w ofhydrophilic surfactants, free of PEG-40 hydrogenated castor oil, lessthan 535 mg of PEG-40 hydrogenated castor oil, less than about 4.5% w/wof PEG-40 hydrogenated castor oil, less than about 20.5% w/w of PEG-40hydrogenated castor oil, less than about 25.5% w/w of PEG-40hydrogenated castor oil, less than 37.5% w/w of PEG-40 hydrogenatedcastor oil, from about 26.0% w/w to about 29.8% w/w of PEG-40hydrogenated castor oil, greater than about 4.9% w/w of PEG-40hydrogenated castor oil, greater than about 20.8% w/w of PEG-40hydrogenated castor oil, greater than about 30.2% w/w of PEG-40hydrogenated castor oil, and greater than about 40.0% w/w of PEG-40hydrogenated castor oil.

In one embodiment, the present oral compositions can comprise at leastone of free of PEG-35 castor oil, less than about 11.8% w/w of PEG-35castor oil, less than about 12.8% w/w of PEG-35 castor oil, less thanabout 22.8% w/w of PEG-35 castor oil, less than about 24.7% w/w ofPEG-35 castor oil, less than about 25.8% w/w of PEG-35 castor oil, lessthan about 37.5% w/w of PEG-35 castor oil, less than about 36.4% w/w ofPEG-35 castor oil, from about 13.2% w/w to about 26.8% w/w of PEG-35castor oil from about 23.2% w/w to about 27.8% w/w of PEG-35 castor oil,greater than about 12.2% w/w of PEG-35 castor oil, greater than about25.3% w/w of PEG-35 castor oil, greater than about 27.3% w/w of PEG-35castor oil, greater than about 28.3% w/w of PEG-35 castor oil, greaterthan about 36.8% w/w of PEG-35 castor oil, and greater than about 40.0%w/w of PEG-35 castor oil.

In one embodiment, the present oral compositions can comprise at leastone of free of caprylocaproyl polyoxyl-8 glycerides, free of LABRASOL,less than about 62.5% w/w of caprylocaproyl polyoxyl-8 glycerides, andgreater than 63.5% w/w of caprylocaproyl polyoxyl-8 glycerides.

In one embodiment, the present oral compositions can comprise at leastone of free of PEG-20 corn glycerides (e.g. CROVOL M-40).

In one embodiment, the present oral compositions can comprise at leastone of free of tocopherol polyethylene glycol succinate (TPGS), lessthan about 2.1% w/w of tocopherol polyethylene glycol succinate, lessthan about 49.4% w/w of tocopherol polyethylene glycol succinate, lessthan about 70.5% w/w of tocopherol polyethylene glycol succinate,succinate, greater than about 2.5% w/w of tocopherol polyethylene glycolsuccinate, greater than about 49.8% w/w of tocopherol polyethyleneglycol succinate, and greater than 71.5% w/w of tocopherol polyethyleneglycol.

In one embodiment, the present oral compositions can comprise at leastone of free of alpha-tocopherol, less than about 7.7% w/w ofalpha-tocopherol, less than about 26.5% w/w of alpha-tocopherol, lessthan about 53.5% w/w of alpha-tocopherol, less than about 58.5% w/w ofalpha-tocopherol, less than about 59.5% w/w of alpha-tocopherol, lessthan about 61.5% w/w of alpha-tocopherol, from about 8.0% w/w to about44.5% w/w of alpha-tocopherol, from about 27.5% w/w to about 58.5% w/wof alpha-tocopherol, from about 54.5% w/w to about 64.5% w/w ofalpha-tocopherol, from about 62.5% w/w to about 67.5% w/w ofalpha-tocopherol, from about 63.2% w/w to about 68.0% w/w ofalpha-tocopherol, from about 59.5% w/w to about 77.5% w/w ofalpha-tocopherol, greater than about 1% alpha-tocopherol, greater thanabout 45.0% w/w of alpha-tocopherol, greater than about 59.5% w/w ofalpha-tocopherol, greater than about 65.5% w/w of alpha-tocopherol,greater than about 68.5% w/w of alpha-tocopherol, and greater than about71.5% w/w of alpha-tocopherol.

In one embodiment, the present oral compositions can comprise less atleast one of than 50% w/w of medium chain monoglycerides, free of mediumchain mono-/di-glycerides.

In one embodiment, the present oral compositions can comprise at leastone of free of caprylic/capric glycerides (e.g. CAPMUL MCM), less thanabout 6.7% w/w of caprylic/capric glycerides, less than about 7.8% w/wof caprylic/capric glycerides, less than about 65.0% w/w ofcaprylic/capric glyceride, less than about 73.0% w/w of caprylic/capricglycerides, less than about 80.5% w/w of caprylic/capric glycerides,less than about 82.0% w/w of caprylic/capric glycerides, less than about83.0% w/w of caprylic/capric glycerides, greater than about 7.0% w/w ofcaprylic/capric glycerides, greater than about 9.0% w/w ofcaprylic/capric glycerides, greater than about 10.0% w/w ofcaprylic/capric glycerides, greater than about 66.0% w/w ofcaprylic/capric glycerides, greater than about 74.0% w/w ofcaprylic/capric glycerides, and greater than about 81.0% w/w ofcaprylic/capric glycerides, greater than about 83.0% w/w ofcaprylic/capric glycerides, and greater than 84.0% w/w ofcaprylic/capric glycerides.

In one embodiment, the present oral compositions can comprise at leastone of free of glyceryl mono-/di-caprylates (e.g. IMWITOR 988), lessthan about 10.5% w/w of glyceryl mono-/di-caprylates, from about 11.2%w/w to about 25.5% w/w of glyceryl mono-/di-caprylates, from about 26.0%w/w to about 44.5% w/w of glyceryl mono-/di-caprylates, and greater thanabout 45.5% w/w of glyceryl mono-/di-caprylates.

In one embodiment, the present oral compositions can comprise at leastone of free of lipophilic surfactants, free of linoleoyl polyoxyl-6glycerides (e.g. LABRAFIL M2125 CS), greater than 1.1% w/w of lipophilicsurfactants, and greater than 1.1% w/w of linoleoyl polyoxyl-6glycerides.

In one embodiment, the present oral compositions can comprise at leastone of free of glyceryl monolinoleate (e.g. MAISINE CC) (previouslyknown as MAISINE 35-1), less than about 8.4% w/w of glycerylmonolinoleate, from about 8.8% w/w to about 19.5% w/w of glycerylmonolinoleate, and greater than about 20.5% w/w of glycerylmonolinoleate.

In one embodiment, the present oral compositions can comprise at leastone of free of propylene glycol monolaurate (e.g. LAUROGLYCOL), lessthan about 36.8% w/w of propylene glycol monolaurate, and greater thanabout 37.2% w/w of propylene glycol monolaurate.

In one embodiment, the present oral compositions can comprise at leastone of free of terpene, free of d-limonene, less than about 4.0% w/w ofterpene, and greater than about 4.5% w/w of terpene.

In one embodiment, the present oral compositions can comprise at leastone of free of medium chain triglycerides, free ofcaprylic/capric/lauric triglycerides (e.g. CAPTEX 350, MIGLYOL 812),less than about 64.5% w/w of medium chain triglycerides, and greaterthan about 66.0% w/w of medium chain triglycerides.

In one embodiment, the present oral compositions can comprise at leastone of free of glyceryl caprylate (e.g. CAPMUL 708G), less than about83.0 w/w of glyceryl caprylate, less than about 71.0% w/w of glycerylcaprylate, less than about 72.0% w/w of glyceryl caprylate, greater thanabout 72.5% w/w of glyceryl caprylate, greater than about 76.5% w/w ofglyceryl caprylate, and greater than about 85.0% w/w of glycerylcaprylate.

In one embodiment, the present oral compositions can comprise at leastone of free of edible oil, free of peanut oil, free of sunflower oil,free of olive oil, free of almond oil, free of sesame oil, and free ofcolza oil.

In one embodiment, the present oral compositions can comprise at leastone of free of digestible oil, free of fractionated coconut oil, free ofsoybean oil, less than about 15.8% w/w of fractionated coconut oil, fromabout 17.4% w/w to about 23.8% w/w of fractionated coconut oil, greaterthan about 24.2% w/w of fractionated coconut oil, less than about 15.8%w/w of soybean oil, and greater than about 16.2% w/w of soybean oil.

In one embodiment, the present oral compositions can comprise at leastone of free of lipophilic solidifying agents, free of hydrogenatedcastor oil, less than 4.9% w/w of hydrogenated castor oil, and greaterthan 5.1% w/w of hydrogenated castor oil.

The compositions can have a daily dose of varying amounts. In oneaspect, the therapeutically effective amount of thepregn-4-ene-3,20-dione can be orally administered from one time totwelve times per day. In one example, the daily dose of thetherapeutically effective amount of the pregn-4-ene-3,20-dione cancomprise from about 10 mg to about 400 mg or 25 mg to 150 mg. In anotherexample, the daily dose of the pregn-4-ene-3,20-dione can be a fixeddose of from about 10 mg to about 3400 mg. In another example, the dailydose of the pregn-4-ene-3,20-dione can be a fixed dose of from about 10mg to about 500 mg. In another example, the daily dose of thepregn-4-ene-3,20-dione can be a fixed dose of from about 10 mg to about2500 mg. In another example, the daily dose of thepregn-4-ene-3,20-dione can be a fixed dose of from about 10 mg to about1500 mg. In another example, the daily dose of thepregn-4-ene-3,20-dione can be a fixed dose of from about 10 mg to about1000 mg. In another example, the daily dose of thepregn-4-ene-3,20-dione can be a fixed dose of from about 10 mg to about500 mg. In yet another aspect, a daily dose of thepregn-4-ene-3,20-dione can be administered in a capsule form comprisingfrom 1-4 capsules.

In one embodiment the daily dose of therapeutically effective amount ofthe pregn-4-ene-3,20-dione can comprise at least one of about 25 mg,about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about55 mg, about 60 mg, about 65 mg, about 70 mg about 75, mg about 80, mgabout 85, mg about 90 mg about 95 mg, about 100 mg, about 110 mg, about120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about195 mg, and about 200 mg, or any amount within a range from about 25 mgto about 200 mg.

In another aspect, a daily dose of the composition can provide: a3α-OH-5α-pregnan-20-one maximum serum concentration level (C_(max)) ofgreater than about 8 ng/ml, about 10 ng/ml, about 12 ng/ml, about 15ng/ml, about 18 ng/ml, about 20 ng/ml, about 25 ng/ml, about 30 ng/ml,about 35 ng/ml, about 40 ng/ml, about 45 ng/ml, about 50 ng/ml, about 60ng/ml, about 70 ng/ml, about 80 ng/ml, about 90 ng/ml, or any maximumserum concentration level within a range from about 8 ng/ml to about 90ng/ml.

In another aspect, a daily dose of the composition can provide a3α-OH-5β-pregnan-20-one maximum serum concentration level (C_(max)) ofgreater than about 6 ng/ml, about 8 ng/ml, about 10 ng/ml, about 12ng/ml, about 15 ng/ml, about 18 ng/ml, about 20 ng/ml, about 25 ng/ml,about 30 ng/ml, about 35 ng/ml, about 40 ng/ml, about 45 ng/ml, about 50ng/ml, about 60 ng/ml, about 70 ng/ml, about 80 ng/ml, about 90 ng/ml,or any maximum serum concentration level within a range from about 6ng/ml to about 90 ng/ml.

In another aspect, a daily dose of the composition can provide: a3β-OH-5α-pregnan-20-one maximum serum concentration level (C_(max)) ofgreater than about 2.5 ng/ml.

In another aspect, a daily dose of the composition can provide a3β-OH-5β-pregnan-20-one maximum serum concentration level (C_(max)) ofgreater than about 2.0 ng/ml.

In one example, an oral pharmaceutical composition comprisingpregn-4-ene-3,20-dione can be formulated in a liquid (e.g., a solution,a suspension, an emulsion, a drink, or the like) or in encapsulatedgelatin capsule dosage forms or as a tablet. The gelatin capsule can bea soft gelatin capsule or a hard gelatin capsule. The hard gelatincapsule can be a two-piece, standard gelatin capsule including a firstcapsule portion bottom and a second capsule portion top. The softgelatin (or other) capsule can be a two-piece capsule wherein twoportions are sealed together or a one-piece that is hermetically sealedcapsule.

In one aspect, the amount of pregn-4-ene-3,20-dione per capsule canrange from about 10 mg to about 400 mg, from about 10 mg to about 200 mgor from about 25 mg to about 150 mg. In one example, the amount ofpregn-4-ene-3,20-dione administered to a subject can be about 10 mg,about 15 mg, about 20 mg, about 25 mg, 30 mg, about 35 mg, about 40 mg,about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg,about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg,about 200 mg, or any amount within a range from about 10 mg to about 200mg.

In one aspect, the capsule fill amount of the oral pharmaceuticalcomposition can range from about 100 mg to about 1400 mg, about 300 mgto about 1300 mg, or about 400 mg to about 1400 mg. In further aspects,the capsule fill amount of the oral pharmaceutical composition can beabout 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg,about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg,about 900 mg, about 950 mg, about 1,000 mg, about 1,050 mg, about 1,100mg, about 1,150 mg, about 1,200 mg, about 1,250 mg, about 1,300 mg,about 1,350 mg, about 1,400 mg, or any amount within a range from about200 mg to about 1400 mg.

In one aspect, the amount of pregn-4-ene-3,20-dione in the compositioncan range from about 1 weight percent (wt %) to about 9 wt %, about 10wt % to about 19 wt %, or about 20 wt % to about 25 wt % of thecomposition. In a further aspect, a subject can be administered theamount of pregn-4-ene-3,20-dione with about 1 wt %, about 1.5 wt %,about 2 wt %, about 2.5 wt %, about 3 wt %, about 3.5 wt %, about 4 wt%, about 4.5 wt %, about 5 wt %, about 5.5 wt %, about 6 wt %, about 6.5wt %, about 7 wt %, about 7.5 wt %, about 8 wt %, about 8.5 wt %, about9 wt %, about 9.5 wt %, about 10 wt %, about 11 wt %, about 12 wt %,about 13 wt %, about 14 wt %, about 15 wt %, about 16 wt %, about 17 wt%, about 18 wt %, about 19 wt %, about 20 wt %, about 21 wt %, about 22wt %, about 23 wt %, about 24 t %, about 25 wt % of the compositiontotal fill amount or any wt % of the composition total fill amountwithin a range from about 1% to about 25%.

In other aspect, the pregn-4-ene-3,20-dione can be administered to asubject (e.g., males and females) to provide a therapeutically effectiveamount of 3α-OH-5α-pregnan-20-one or 3α-OH-5β-pregnan-20-one. In oneexample, the pregn-4-ene-3,20-dione in the oral compositions can have atotal daily dose that ranges from about 10 mg to about 3400 mg, andabout 10 mg, about 15 mg, about 20 mg, about 25 mg, 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg,about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg,about 190 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg,about 800 mg, about 1,000 mg, about 1,200 mg, about 1,500 mg, about1,800 mg, about 2,000 mg, about 2,400 mg, about 2,800 mg, about 3,000mg, about 3,400 mg, or any amount within a range from about 10 mg toabout 3400 mg.

In another aspect, the amount of pregn-4-ene-3,20-dione in a dosage form(e.g., in a capsule) from the oral pharmaceutical composition can rangefrom about 10 mg to about 400 mg, from about 10 mg to about 200 mg orfrom about 25 mg to about 150 mg or from about 25 mg to about 100 mg. Insome aspects, the amount of pregn-4-ene-3,20-dione administered to asubject can be about 10 mg, about 15 mg, about 20 mg, about 25 mg, 30mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg,about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170mg, about 180 mg, about 190 mg, about 200 mg, or any amount within arange from about 10 mg to about 200 mg.

To receive a target amount of the GABA receptor PAM(s) (e.g.,3α-OH-5α-pregnan-20-one or 3α-OH-5β-pregnan-20-one or both) per singledose, in some aspects, the subject can be administeredpregn-4-ene-3,20-dione in amounts of from 10 mg to 400 mg, such as about10 mg, about 15 mg, about 20 mg, about 25 mg, 30 mg, about 35 mg, about40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or anyamount within a range from about 10 mg to about 400 mg or from about 25mg to about 200 mg.

In one aspect, the therapeutically effective amount of thepregn-4-ene-3,20-dione can be orally administered once daily in anyrecited amount until the CNS disease or condition is treated. In oneaspect, the oral compositions can be administered in the morning,afternoon, evening, or before bedtime. In another aspect, the oralcompositions can be administered 5 hours, 4 hours, 3 hours, 2 hours, or1 hour before bedtime, or at bedtime.

In other aspects, the oral pharmaceutical composition and/or oral dosageforms can be administered twice daily in any of the above noted amountsuntil the disease or condition is treated. The oral compositions can beadministered in the morning and evening, or 12 hours apart. In yetfurther aspects, the oral pharmaceutical composition or oral dosage formcan be administered greater than or equal to three times daily in any ofthe recited amounts until the disease or condition is treated. The oralcompositions or dosage forms can be administered every 8 hours, every 6hours, every 4 hours, every 3 hours, every 2 hours, or every 1 hour.

In one aspect, the therapeutically effective amount of thepregn-4-ene-3,20-dione can be orally administered to the subjectaccording to a dosage regimen of at least once per day for a specifiedduration of from about a single day to about 3 months. In anotheraspect, the oral pharmaceutical composition can be administered for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 12 days, 14 days, 16 days, 18 days, 20 days, 21 days, 22 days, 24days, 26 days, or 28, or 30 days until the disease or condition istreated. In one aspect, the oral pharmaceutical compositions can beadministered for 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks until thedisease or condition is treated. In another aspect, the oralpharmaceutical can be administered for 1 month, 2 months, or 3 monthsuntil the disease or condition is treated.

In one aspect, the oral pharmaceutical composition or dosage form can beadministered with or without titration. In one aspect, the oralpharmaceutical compositions can be up-titrated by 50%, 100%, 150%, 200%,300%, 400%, 500% or more than the initial dose. In another aspect, theoral pharmaceutical compositions can be down-titrated by 50% or morethan the initial dose. In another aspect, the oral pharmaceuticalcompositions can be up-titrated and subsequently down-titrated and/orvice versa. In an aspect, the oral pharmaceutical compositions can beadministered with the fixed dose or the consistent dose as the initialdose.

In one aspect, the oral pharmaceutical composition or dosage form can betitrated to a subsequent pregn-4-ene-3,20-dione dose based on apharmacokinetic or pharmacodynamic response to an initial dose by asubject. In one example, the composition or oral dosage form can beorally administered in an initial pregn-4-ene-3,20-dione dose of fromabout 10 mg to about 200 mg and titrated to a maintenancepregn-4-ene-3,20-dione dose that is about 25% to about 100% higher thanthe initial dose. In one example, the pregn-4-ene-3,20-dione dose can beincreased or decreased from about 0.25× to about 4× from an initialpregn-4-ene-3,20-dione dose to a pregn-4-ene-3,20-dione maintenancedose.

In another aspect the oral pharmaceutical compositions or dosage formscan be administered with or without food, such as meal, snacks,appetizers, or drinks. In one example, administration without food canbe during a fasting period of the subject. Food can include variousforms including: no fat and no calorie; no fat and low calorie; no fatand medium calorie; no fat and high calorie; low fat and low calorie;low fat and medium calorie; low fat and high calorie; medium fat and lowcalorie; medium fat and medium calorie; medium fat and high calorie;high fat and medium calorie; or high fat and high calorie. In oneaspect, administration with food can be: without high-fat food; with ameal with at least about 5% calories from fat; with a meal with lessthan about 20% calories from fat; with a meal having from about 20% toabout 35% calorie content from fat; or with a meal having from about 35%to about 60% calorie content from fat. The amount of fat and caloriescan be categorized via the regulations for foods under the Federal Food,Drug, and Cosmetic Act and its amendments.

Methods

In absence of the analyte assay based on chromatography-combined massspectrometry method (e.g. LC-MS/MS or GC-MS), serum neurosteroidmeasurements for pregn-4-ene-3,20-dione, and its PAM or NAM metabolitesbased on an immunoassay are not accurate because the assay is typicallynot specific to the target analyte. Consequently, data and resultsrelated to oral pregn-4-ene-3,20-dione and its neurosteroid, PAM (e.g.,3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one) or NAM (e.g.,3β-OH-5α-pregnan-20-one, 3β-OH-5β-pregnan-20-one) metabolites withrespect to levels of PAM and/or NAM generation or the adequacy of PAMand/or NAM levels for desirable GABA receptor modulation. It has beendiscovered that inducing immediate conversion post oral administrationof the pregn-4-ene-3,20-dione prodrug in favor of high PAM and low NAMgeneration in the GI tract through the present compositions and methodscan be effective to produce desirable levels of neurosteroids to treatCNS depression disorders.

In one embodiment, a method of treating a CNS disorder in a subject caninclude orally administering to the subject, composition comprising atherapeutically effective amount of pregn-4-ene-3,20-dione that providesan amount of 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, orboth that is sufficient to treat the CNS depression disorder. In oneaspect, a method of treating a CNS disorder in a subject can includeorally administering to the subject, composition comprising atherapeutically effective amount of pregn-4-ene-3,20-dione that providesan amount of 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, orboth while generating 20% to 100% altered serum levels of isomeric NAM,3β-OH-5β-pregnan-20-one or a 3β-OH-5α-pregnan-20-one, that is sufficientto treat the CNS depression disorder. In one aspect, the therapeuticallyeffective amount of pregn-4-ene-3,20-dione can be in a form thatprovides a therapeutically effective amount of either3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or a combinationthereof for treating the CNS depression disorder in the subject. Inanother aspect, the therapeutically effective amount ofpregn-4-ene-3,20-dione can be in a form that provides a therapeuticallyeffective amount of either 3α-OH-5α-pregnan-20-one, or3α-OH-5β-pregnan-20-one, or a combination thereof for treating the CNSdepression disorder in the subject with at least 20% to 100% alteredserum levels of isomeric NAM, 3β-OH-5β-pregnan-20-one or a3β-OH-5α-pregnan-20-one, for treating the CNS depression disorder in thesubject. In another aspect, the pregn-4-ene-3,20-dione can be combinedwith a carrier that is sufficient to provide a therapeutically effectiveamount of either 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, ora combination thereof for treating the CNS disorder in the subject. Inanother aspect, the pregn-4-ene-3,20-dione can be combined with acarrier that is sufficient to provide a therapeutically effective amountof either 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or acombination thereof with at least 20% to 100% altered serum levels ofisomeric NAM, 3β-OH-5β-pregnan-20-one or a 3β-OH-5α-pregnan-20-one, fortreating the CNS depression disorder in the subject.

In another aspect, the pregn-4-ene-3,20-dione can be in a form thatincreases formation of either 3α-OH-5α-pregnan-20-one, or3α-OH-5β-pregnan-20-one, or both as compared to an equivalent amount ofa micronized administration. In one example, the formation of either3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or both can beincreased by up to about 8 times as compared to an equivalent amount ofa micronized administration.

In one aspect, the CNS disorder can be selected from the groupconsisting of: post-partum depression, postpartum blues, postpartumsubstance use addiction disorder, Major Depressive Disorder with aperipartum onset, the like, or combinations thereof.

In another embodiment, a method of treating a CNS disorder in a subject,can include orally administering to the subject, a therapeuticallyeffective amount of pregn-4-ene-3,20-dione that provides an amount ofGABA receptor modulating neurosteroid metabolites that is sufficient totreat the CNS disorder. In one aspect, the GABA receptor bindingpregn-4-ene-3,20-dione metabolites can be selected from the groupconsisting of: 3α-OH-5α-pregnan-20-one, a PAM, or3α-OH-5β-pregnan-20-one, a PAM, or 3β-OH-5α-pregnan-20-one, a NAM, or,3β-OH-5β-pregnan-20-one, a NAM, the like, or combinations thereof. Inanother aspect, the GABA receptor binding pregn-4-ene-3,20-dionemetabolites can be selected from the group consisting of:3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, the like, orcombinations thereof. In another aspect, the GABA receptor bindingpregn-4-ene-3,20-dione metabolites can be selected from the groupconsisting of: 3β-OH-5α-pregnan-20-one, 3β-OH-5β-pregnan-20-one, thelike, or combinations thereof.

In one aspect, the subject can have an acute CNS disorder, an episodicCNS disorder, an intermittent CNS disorder, a sub-chronic CNS disorder,a chronic CNS disorder, or combinations thereof. When the CNS disorderis sub-chronic or chronic, the dosage regimen can range from at leastonce per day for a specified duration of from about a single day toabout 3 months, or more than 3 months.

The subjects, in one embodiment, in need of the oral compositionsdescribed herein can have CNS disorders, such as depression disorders(e.g., postpartum depression, postpartum substance addiction disorder,major depressive disorder, treatment resistant depression, perinataldepression, perimenopausal or postmenopausal depression),

In some embodiments, the oral compositions comprising can be used forthe treatment, reduction, or enhancement of conditions, symptoms, ordiseases associated with CNS disorders described hereof can be males orfemales. In one aspect, subjects can be adolescent males or adult males.In further aspects, subjects can be adolescent, adult, female ofchildbearing age, pre-menopausal, perinatal, postpartum, pregnant,peri-menopausal, or post-menopausal females. In yet another aspect, thesubject may not be exhibiting symptoms, but can have diseases associatedwith CNS disorders described hereof

Pharmacokinetics and Pharmacodynamics

Serum neurosteroid measurements for pregn-4-ene-3,20-dione, and its PAMor NAM metabolites based on an immunoassay are not accurate because theassay is typically not specific to the target analyte. To measure thetarget analyte, the assay should be based on chromatography-combinedmass spectrometry method (LC-MS/MS or GC-MS), which can provide reliabledata to assess the true pharmacokinetic and pharmacodynamic potential ofpregn-4-ene-3,20-dione and its PAM and NAM metabolites.

In one example, a single dose administration of the composition or oraldosage form to a subject can provide a T_(max) forpregn-4-ene-3,20-dione, or 3α-OH-5α-pregnan-20-one, or3α-OH-5β-pregnan-20-one in less than about 1.5 hours, less than about 2hours, less than about 3 hours, or less than about 4 hours after theoral administration.

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a reduction time of theC_(max) level to one half of the C_(max) level for3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one within: about 1hour, about 3 hours, about 5 hours, about 6 hours, or about 8 hours ofthe oral administration.

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a 3α-OH-5α-pregnan-20-onemaximum serum concentration level (C_(max)) of greater than about8/ng/ml, about 10 ng/ml, about 12 ng/ml, about 15 ng/ml, about 18 ng/ml,about 20 ng/ml, about 25 ng/ml, about 30 ng/ml, about 35 ng/ml, about 40ng/ml, about 45 ng/ml, about 50 ng/ml, about 60 ng/ml, about 70 ng/ml,about 80 ng/ml, about 90 ng/ml, or maximum serum concentration levelwithin a range from about 8 ng/ml to about 90 ng/ml.

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a 3α-OH-5β-pregnan-20-onemaximum serum concentration level (C_(max)) of greater than about 6ng/ml, about 8 ng/ml, about 10 ng/ml, about 12 ng/ml, about 15 ng/ml,about 18 ng/ml, about 20 ng/ml, about 25 ng/ml, about 30 ng/ml, about 35ng/ml, about 40 ng/ml, about 45 ng/ml, about 50 ng/ml, about 60 ng/ml,about 70 ng/ml, about 80 ng/ml, about 90 ng/ml, or maximum serumconcentration level within a range from about 8 ng/ml to about 90 ng/ml.

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a ratio of C_(max) for3α-OH-5α-pregnan-20-one (ng/ml) to C_(max) for pregn-4-ene-3,20-dione(ng/ml) of greater than about 1:1, greater than about 2:1, greater thanabout 3:1, greater than about 4:1, greater than about 5:1, greater thanabout 10:1, greater than about 20:1, greater than about 30:1, greaterthan about 40:1, or greater than about 50:1

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a ratio of C_(max) for3α-OH-5β-pregnan-20-one (ng/ml) to C_(max) for pregn-4-ene-3,20-dione(ng/ml) of greater than about 1:1, greater than about 2:1, greater thanabout 3:1, greater than about 4:1, greater than about 5:1, greater thanabout 10:1, greater than about 20:1, greater than about 30:1, greaterthan about 40:1, or greater than about 50:1.

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a ratio of a sum of C_(max)for 3α-OH-5α-pregnan-20-one (ng/ml) and 3α-OH-5β-pregnan-20-one (ng/ml)to C_(max) for pregn-4-ene-3,20-dione (ng/ml) of greater than about 2:1,greater than about 3:1, greater than about 4:1, greater than about 5:1,greater than about 6:1, greater than about 7:1, greater than about 8:1,greater than about 9:1, greater than about 10:1, greater than about20:1, greater than about 30:1, greater than about 40:1, greater thanabout 50:1, greater than about 60:1, greater than about 70:1, greaterthan about 80:1, greater than about 90:1, or greater than 100:1.

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a ratio of C_(max) for3α-OH-5α-pregnan-20-one (ng/ml) to C_(max) for 3β-OH-5α-pregnan-20-one(ng/ml) of from about 1.2 to about 10.0.

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a ratio of C_(max) for3α-OH-5β-pregnan-20-one (ng/ml) to C_(max) for 3β-OH-5β-pregnan-20-one(ng/ml) of from about 1.2 to about 10.0.

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a ratio of a sum of C_(max)for 3α-OH-5α-pregnan-20-one (ng/ml) and 3α-OH-5β-pregnan-20-one (ng/ml)to a sum of C_(max) for 3β-OH-5α-pregnan-20-one (ng/ml) and3β-OH-5β-pregnan-20-one (ng/ml) of about 1.2 to about 10.0.

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a ratio of C_(max) of3α-OH-5α-pregnan-20-one (ng/ml) to daily dose of pregn-4-ene-3,20-dione(mg) of from about 7.5×10⁻⁸/ml to about 2.5×10⁻⁶/ml. In another example,a single dose administration of the composition to a subject can providea ratio of C_(max) of 3α-OH-5β-pregnan-20-one (ng/ml) to daily dose ofpregn-4-ene-3,20-dione (mg) of from about 5.0×10⁻⁸/ml to about2.5×10⁻⁶/ml. In another example, a single dose administration of thecomposition to a subject can provide a ratio of sum of C_(max) for3α-OH-5α-pregnan-20-one (ng/ml) and 3α-OH-5β-pregnan-20-one (ng/ml) todaily dose of pregn-4-ene-3,20-dione (mg) of from about 1.3×10⁻⁷/ml toabout 5.0×10⁻⁶/ml.

In one example, the oral compositions or dosage forms and methods canprovide a C_(max) of 3α-OH-5α-pregnan-20-one of about 8 ng/ml to 90ng/ml or about 18 ng/ml to 80 ng/ml, such as at least about 18 ng/ml,about 20 ng/ml, about 22 ng/ml, about 25 ng/ml, about 30 ng/ml, about 35ng/ml, about 40 ng/ml, about 45 ng/ml, about 50 ng/ml, about 55 ng/ml,about 60 ng/ml, about 65 ng/ml, about 70 ng/ml, about 75 ng/ml, about 80ng/ml, or greater than about 80 ng/ml. In another example, the oralcompositions and methods can provide a C_(max) of3α-OH-5β-pregnan-20-one of about 6 ng/ml-90 ng/ml or about 11 ng/ml-80ng/ml, such as at least about 11 ng/ml, about 13 ng/ml, about 15 ng/ml,about 18 ng/ml, about 20 ng/ml, about 25 ng/ml, about 30 ng/ml, about 35ng/ml, about 40 ng/ml, about 45 ng/ml, about 50 ng/ml, about 55 ng/ml,about 60 ng/ml, about 65 ng/ml, about 70 ng/ml, or greater than about 80ng/ml. In yet further example, the oral compositions and methods canprovide a total C_(max) of 3α-OH-5α-pregnan-20-one and3α-OH-5β-pregnan-20-one of about 14 ng/ml-180 ng/ml or about 28ng/ml-160 ng/ml, such as at least about 28 ng/ml, about 30 ng/ml, about35 ng/ml, about 40 ng/ml, about 45 ng/ml, about 50 ng/ml, about 60ng/ml, about 70 ng/ml, about 80 ng/ml, about 90 ng/ml, about 100 ng/ml,about 110 ng/ml, about 120 ng/ml, about 130 ng/ml, about 140 ng/ml,about 150 ng/ml, or greater than about 160 ng/ml.

In another example, a single dose administration of the oralcompositions or dosage forms and methods to a subject can provide aratio of C_(max) for 3α-OH-5β-pregnan-20-one (ng/ml) to C_(max) forpregn-4-ene-3,20-dione (ng/ml) of greater than about 1:1, greater thanabout 2:1, greater than about 3:1, greater than about 4:1, greater thanabout 5:1, greater than about 6:1, greater than about 7:1, greater thanabout 8:1, greater than about 9:1, or greater than about 10:1, greaterthan about 20:1, greater than about 30:1, greater than about 40:1, orgreater than about 50:1.

In another example, a single dose administration of the oralcompositions or dosage forms and methods to a subject can provide aratio of C_(max) for 3α-OH-5α-pregnan-20-one (ng/ml) to C_(max) forpregn-4-ene-3,20-dione (ng/ml) of greater than about 1:1, greater thanabout 2:1, greater than about 3:1, greater than about 4:1, greater thanabout 5:1, greater than about 6:1, greater than about 7:1, greater thanabout 8:1, greater than about 9:1, or greater than about 10:1, greaterthan about 20:1, greater than about 30:1, greater than about 40:1, orgreater than about 50:1.

In another example, a single dose administration of the oralcompositions or dosage forms and methods to a subject can provide aratio of a sum of C_(max) for 3α-OH-5α-pregnan-20-one (ng/ml) and3α-OH-5β-pregnan-20-one (ng/ml) to C_(max) for pregn-4-ene-3,20-dione(ng/ml) of greater than about 2:1, greater than about 3:1, greater thanabout 4:1, greater than about 5:1, greater than about 6:1, greater thanabout 7:1, greater than about 8:1, greater than about 9:1, greater thanabout 10:1, greater than about 20:1, greater than about 30:1, greaterthan about 40:1, greater than about 50:1, greater than about 60:1,greater than about 70:1, greater than about 80:1, greater than about90:1, or greater than 100:1.

In another example, a single dose administration of the oralcompositions or dosage forms and methods to a subject can provide aratio of C_(max) of 3α-OH-5α-pregnan-20-one (ng/ml) to daily dose ofpregn-4-ene-3,20-dione (mg) of from about 7.5×10⁻⁸/ml to about2.5×10⁻⁶/ml. In another example, a single dose administration of theoral compositions or dosage forms and methods to a subject can provide aratio of C_(max) of 3α-OH-5β-pregnan-20-one (ng/ml) to daily dose ofpregn-4-ene-3,20-dione (mg) of from about 5.0×10⁻⁸/ml to about2.5×10⁻⁶/ml. In another example, a single dose administration of theoral compositions or dosage forms and methods to a subject can provide aratio of sum of C_(max) for 3α-OH-5α-pregnan-20-one (ng/ml) and3α-OH-5β-pregnan-20-one (ng/ml) to daily dose of pregn-4-ene-3,20-dione(mg) of from about 1.3×10⁻⁷/ml to about 5.0×10⁻⁶/ml.

In another example, a single dose administration of the oralcompositions or dosage forms and methods to a subject can provide aratio of C_(max) for 3α-OH-5α-pregnan-20-one (ng/ml) to C_(max) for3β-OH-5α-pregnan-20-one (ng/ml) of from about 1.2 to about 10.0.

In another example, a single dose administration of the oralcompositions or dosage forms and methods to a subject can provide aratio of C_(max) for 3α-OH-5β-pregnan-20-one (ng/ml) to C_(max) for3β-OH-5β-pregnan-20-one (ng/ml) of from about 1.2 to about 10.0.

In another example, a single dose administration of the oralcompositions or dosage forms and methods to a subject can provide aratio of a sum of C_(max) for 3α-OH-5α-pregnan-20-one (ng/ml) and3α-OH-5β-pregnan-20-one (ng/ml) to a sum of C_(max) for3β-OH-5α-pregnan-20-one (ng/ml) and 3β-OH-5β-pregnan-20-one (ng/ml) ofabout 1.2 to about 10.0.

In another example, a single dose administration of the composition ororal dosage form and methods to a subject can provide a daily C_(avg) of3α-OH-5α-pregnan-20-one or 3α-OH-5β-pregnan-20-one serum concentrationof greater than about 4 ng/ml.

In another example, a single dose administration of the composition ororal dosage form and methods to a subject can provide sum of dailyC_(avg) of 3α-OH-5β-pregnan-20-one and 3α-OH-5β-pregnan-20-one serumconcentration of greater than about 8 ng/ml.

In another example, a single dose administration of the composition ororal dosage form and methods to a subject can provide a ratio of dailyC_(avg) for 3α-OH-5α-pregnan-20-one (ng/ml) to daily C_(avg) forpregn-4-ene-3,20-dione (ng/ml) of greater than about 1:1, greater thanabout 2:1, greater than about 3:1, greater than about 4:1, greater thanabout 5:1, greater than about 6:1, greater than about 7:1, greater thanabout 8:1, greater than about 9:1, or greater than about 10:1, greaterthan about 20:1, greater than about 30:1, greater than about 40:1, orgreater than about 50:1.

In another example, a single dose administration of the composition ororal dosage form and methods to a subject can provide a ratio of dailyC_(avg) for 3α-OH-5β-pregnan-20-one (ng/ml) to daily C_(avg) forpregn-4-ene-3,20-dione (ng/ml) of greater than about 1:1, greater thanabout 2:1, greater than about 3:1, greater than about 4:1, greater thanabout 5:1, greater than about 6:1, greater than about 7:1, greater thanabout 8:1, greater than about 9:1, or greater than about 10:1, greaterthan about 20:1, greater than about 30:1, greater than about 40:1, orgreater than about 50:1.

In another example, a single dose administration of the composition ororal dosage form and methods to a subject can provide a ratio of a sumof daily C_(avg) for 3α-OH-5α-pregnan-20-one (ng/ml) and3α-OH-5β-pregnan-20-one (ng/ml) to daily C_(avg) forpregn-4-ene-3,20-dione (ng/ml) of greater than about 2:1, greater thanabout 3:1, greater than about 4:1, greater than about 5:1, greater thanabout 6:1, greater than about 7:1, greater than about 8:1, greater thanabout 9:1, greater than about 10:1, greater than about 20:1, greaterthan about 30:1, greater than about 40:1, greater than about 50:1,greater than about 60:1, greater than about 70:1, greater than about80:1, greater than about 90:1, or greater than 100:1.

In another example, a single dose administration of the oralcompositions or dosage forms and methods to a subject can provide aratio of daily C_(avg) of 3α-OH-5α-pregnan-20-one (ng/ml) to daily doseof pregn-4-ene-3,20-dione (mg) of from about 1.0×10⁻⁸/ml to about1.0×10⁻⁶/ml. In another example, a single dose administration of theoral compositions or dosage forms and methods to a subject can provide aratio of daily C_(avg) of 3α-OH-5β-pregnan-20-one (ng/ml) to daily doseof pregn-4-ene-3,20-dione (mg) of from about 1.0×10⁻⁸/ml to about1.0×10⁻⁶/ml. In another example, a single dose administration of theoral compositions or dosage forms and methods to a subject can provide aratio of sum of daily C_(avg) for 3α-OH-5α-pregnan-20-one (ng/ml) and3α-OH-5β-pregnan-20-one (ng/ml) to daily dose of pregn-4-ene-3,20-dione(mg) of from about 2.0×10⁻⁸/ml to about 2.0×10⁻⁶/ml.

In another example, a single dose administration of the composition ordosage form to a subject can provide a treatment that occurs in lessthan about 1 hour or about 2 hours. In one aspect, the oral compositionsand methods can provide the onset of CNS activity in less than about 1hour to about 5 hour, such as about less than 1 hour, about 1 hour about1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5hours, about 4 hours, about 4.5 hours, or about 5 hours.

In another example, a single dose administration of the composition ororal dosage form to a subject can provide a treatment that occurs forgreater than about 2 hours after administration, about 4 hours afteradministration, about 8 hours after administration, about 24 hours afteradministration, or about 2 days after administration. In some aspects,the oral compositions and methods can maintain the duration of CNSactivity for at least from about 1 hour to 24 hours, about 1 day to 30days, about 1 week to 12 weeks, or about 1 month to 6 months. In oneexample, the oral compositions and methods can maintain the duration ofCNS activity from about 1 hour to 24 hours, such as at least about 1hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours,about 11 hours, about 12 hours, about 14 hours, about 16 hours, about 18hours, about 20 hours, about 22 hours, or about 24 hours.

In another example, the duration of CNS activity can be maintained fromabout 1 day to 30 days, such as at least about 1 day, about 2 day, about3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 11 days, about 12 days, about15 days, about 18 days, about 21 days, about 24 days, about 25 days,about 28 days, or about 30 days. In another example, the oralcompositions and methods can maintain the duration of CNS activity fromabout 1 week to 12 weeks, such as at least about 1 week, about 2 weeks,about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, orabout 12 weeks. In yet a further example, the oral compositions andmethods can maintain the duration of CNS activity from about 1 month to6 months, such as at least about 1 month, about 2 months, about 3months, about 4 months, about 5 months, or about 6 months.

A baseline 17-item HAM-D (Hamilton Depression Rating) score of between20 and 25 can be associated with moderate depression and a 17-item HAM-Dscore of greater than about 25 can be associated with severe depression.In one example, oral administration of the composition or dosage form toa subject can reduce a 17-item HAM-D score in a subject by about 3,about 4, about 5, about 6, about 7, about 8, about 9, or about 10, orabout 15, or about 20 as compared to baseline when measured at about 1day to about 45 days after commencement of treatment. In another aspect,the oral compositions and methods can provide a reduction in the HAM-Dscore by at least about 2.0 or 2.5 compared to the score in the placebotreatment (change from baseline), such as by about 2.0, about 2.5, about3.0, about 3.5, about 4.0, about 4.5, about 5.0, or greater than about5.0, when measured post treatment. In one aspect, the oral compositionsand methods can provide a reduction in HAM-D score by least about 1.5 or2.0 compared to the score in the placebo treatment (change frombaseline), such as by about 2.0, about 2.5, about 3.0, about 3.5, about4.0, about 4.5, about 5.0, and greater than about 5.0, at one of 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30 or 45 days when measured after commencementof treatment.

In another example, a single dose administration of the composition ororal dosage form and methods to a subject can induce remission of thedisease through reduction in a 17-item HAM-D total score in a subject(e.g. total score reduced to <=7) as compared to the baseline atcommencement of treatment when measured at about 3 days to about 28 daysafter commencement of treatment.

In another example, a single dose administration of the composition ororal dosage form and methods to a subject can reduce a 17-item HAM-Dscore in a subject by at least about 2, about 3, about 4, about 5, about6, about 7, about 8, about 9, about 10, about 10, about 11, about 12,about 13, about 14, about 15 about 20 as compared to the baseline atcommencement of treatment when measured at about 3 days to about 28 daysafter commencement of treatment. In some examples, the oral compositionsand methods can provide a reduction in HAM-D score by at least about 3.0from the baseline, such as about 3.0, about 3.5, about 4.0, about 4.5,about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about8.0, about 8.5, about 9.0, about 9.5, about 10, or greater than about 10at the efficacy date post treatment. In one example, the oralcompositions and methods can provide a reduction in HAM-D score by atleast about 2.0 or 2.5 from the baseline, such as about 2.0, about 2.5,about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0,about 9.5, about 10, and greater than about 10, at one of 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, or 30 days post administration. In another aspect, theoral compositions or dosage forms and methods can provide a reduction inthe HAM-D score by at least about 2.0 or 2.5 compared to the score inthe placebo treatment (change from baseline), such as by about 2.0,about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, orgreater than about 5.0, when measured post treatment. In one aspect, theoral compositions or dosage forms and methods can provide a reduction inHAM-D score by least about 1.5 or 2.0 compared to the score in theplacebo treatment, such as by about 1.5, about 2.0, about 2.5, about3.0, about 3.5, about 4.0, about 4.5, about 5.0, and greater than about5.0, at one of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 45 days when measuredpost treatment (change from baseline).

In another example, a single dose administration of the composition ororal dosage form and methods to a subject can induce remission of thedisease through reduction in MADRS score as compared to the baseline atcommencement of treatment when measured at about 3 days to about 28 daysafter commencement of treatment. In one aspect, the oral compositionsand methods can provide a reduction from the baseline in MADRS score byat least greater than about 3, about 4, about 5, about 6, about 7, about8, about 9, about 10, about 15, or about 20 as compared to baseline whenmeasured at about 1 day to about 45 days after commencement of treatmentto a subject with MADRS score >20.

In another example, a single dose administration of the composition ororal dosage form and methods to a subject can induce remission of thedisease through reduction in EPDS score as compared to the baseline atcommencement of treatment when measured at about 3 days to about 28 daysafter commencement of treatment. In one aspect, the oral compositionsand methods can provide a reduction from the baseline in MADRS score byat least greater than about 2, about 3, about 4, about 5, about 6, about7, about 8, about 9, or about 10 as compared to baseline when measuredat about 1 day to about 45 days after commencement of treatment to asubject with MADRS score >10.

EXAMPLES

The following examples are provided to promote a clearer understandingof certain invention embodiments, and are in no way meant as alimitation thereon.

Example 1—Pregn-4-ene-3,20-dione Compositions

TABLE 1A Vitamin E or its derivative-comprising compositions Composition1A (w/w %) Component I II III IV Pregn-4-ene-3,20-dione 20-25 15-1910-14 1-9 Vitamin E or its derivative (e.g., 10-80 10-85 10-90  2-99TPGS, tocopherol, tocopherol acetate, tocotrienol, or a combination)Other carrier ingredients* q.s. q.s. q.s. q.s.

TABLE 1B Fatty acid or its salt-comprising compositions Composition 1B(w/w %) Component I II III IV Pregn-4-ene-3,20-dione 20-25 15-19 10-141-9 Fatty acid or its salt (e.g., oleic acid, 30-80 30-85 30-90 30-99linoleic acid, lauric acid, myristic acid, octanoic acid, capric acid,sodium octanoate, sodium caprate, sodium oleate, sodium lauroyllactylate, sodium stearoyl lactylate, sodium laurate, or a combination)Other carrier ingredients q.s. q.s. q.s. q.s.

TABLE 1C Glyceryl fatty acid ester-comprising compositions Composition1C (w/w %) Component I II III IV Pregn-4-ene-3,20-dione 20-25 15-1910-14 1-9 Glyceryl fatty acid ester (e.g., Capmul 30-80 30-85 30-9030-99 MCM, Capmul MCM C8, Capmul 808G, Capmul GMO-50, Capmul 708G,Imwitor 308, Imwitor 382 P, Imwitor 375, Imwitor 742, Imwitor 988,Myvacet 9-45, Maisine 35-1, Maisine CC, or a combination) Other carrieringredients q.s. q.s. q.s. q.s.

TABLE 1D Polyglycerol fatty acid ester-comprising compositionsComposition 1D (w/w %) Component I II III IV Pregn-4-ene-3,20-dione20-25 15-19 10-14 1-9 Polyglycerol fatty acid ester (e.g., 30-80 30-8530-90 30-99 Caprol PGE-860, Plurol Oleique CC 497, Caprol MPGO, Caprol3GO, Caprol 6GC8, Caprol 10G10O, Caprol ET, Drewpol 10-10-O, or acombination) Other carrier ingredients q.s. q.s. q.s. q.s.

TABLE 1E PEG glyceride of fatty acid ester-comprising compositionsComposition 1E (w/w %) Component I II III IV Pregn-4-ene-3,20-dione20-25 15-19 10-14 1-9 PEG glyceride of fatty acid ester (e.g., 30-8030-85 30-90 30-99 Gelucire 44/14, Gelucire 50/13, Acconon CC-6, AccononCO-7, Acconon C-30, Acconon C-80, Acconon E, Lipopeg 2-DL, Labrafac PG,TEFOSE 63, Labrafil M2125CS, Labrafil M1944CS, Labrasol, Acconon MC8-2,Acconon C-44, Acconon C-50, Acconon AKG-6, Labrafil M2130CS, CompritolHD 5 ATO or a combination) Other carrier ingredients q.s. q.s. q.s. q.s.

TABLE 1F Triglyceride-comprising compositions Composition 1F (w/w %)Component I II III IV Pregn-4-ene-3,20-dione 20-25 15-19 10-14 1-9Triglyceride (e.g., Captex 300, Captex 30-80 30-85 30-90 30-99 300 LowC6, Captex 350, Captex 355, Miglyol 808, Miglyol 810, Miglyol 812,Miglyol 818, Miglyol 829, Labrafac Lipophile WL 1349, or a combination)Other carrier ingredients q.s. q.s. q.s. q.s.

TABLE 1G Hydrogenated polyoxyl vegetable oil or glyceride-comprisingcompositions Composition 1G (w/w %) Component I II III IVPregn-4-ene-3,20-dione 20-25 15-19 10-14 1-9 Hydrogenated polyoxylvegetable oil  1-50  1-50  1-50  1-50 or glyceride (e.g., Kolliphor EL,Kolliphor RH40, Etocas 40, Croduret 60, Kolliphor HS 15, Etocas 5,Sterotex, Sterotex HM, Sterotex K, or a combination) Other carrieringredients q.s. q.s. q.s. q.s.

TABLE 1H Propylene glycol fatty acid ester-comprising compositionsComposition 1H (w/w %) Component I II III IV Pregn-4-ene-3,20-dione20-25 15-19 10-14 1-9 Propylene glycol fatty acid ester (e.g., 30-8030-85 30-90 30-99 Lauroglycol 90, Captex 100, Captex 200, Miglyol 840,Neobee M-20, Capmul PG-8, Capmul PG-12, Capmul PG-2L, Capryol 90,Acconon E, or a combination) Other carrier ingredients q.s. q.s. q.s.q.s.

TABLE 1I Edible oil-comprising compositions Composition 1I (w/w %)Component I II III IV Pregn-4-ene-3,20-dione 20-25 15-19 10-14 1-9Edible oil (e.g., peppermint oil, borage 30-80 30-85 30-90 30-99 oil,soybean oil, olive oil, coconut oil, omega-3 oil, castor oil, and so on)Other carrier ingredients q.s. q.s. q.s. q.s.

Other carrier ingredients in Example 1 can be hydrophilic additives,lipophilic additives, co-solvents, other functional additives, orcombinations thereof if needed. Co-solvents can be at least one or acombination of: alcohol, glycerin, glycofural, triacetin, trimethylcitrate, propylene glycol, polyethylene glycol, sorbitol,dimethylacetamide, and dimethylsulfoxide.

Example 2—Pregn-4-ene-3,20-dione Compositions with Lipophilic Additives

TABLE 2A Vitamin E or its derivative-comprising compositions Composition2A (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14Pregn-4-ene-3,20-dione  1-10  1-10  1-10  1-10  1-10  1-10  1-10  1-10 1-10  1-10  1-10  1-10  1-10  1-10 Vitamin E or its derivative (e.g.,30-50 10-22 10-22 10-22 10-22 10-22 10-22 10-22 10-22 10-22 10-22 10-2210-22 10-22 TPGS, tocopherol, tocopherol acetate, tocotrienol,Tocophersolan, and so on) Lipophilic Glyceryl fatty acid ester (e.g.,30-50 30-50 30-50 18-54 additives Capmul MCM C8, Capmul 808G, Imwitor988, Maisine CC, and so on) Polyglycerol fatty acid ester 18-54 68-8930-50 18-54 18-54 (e.g., Caprol PGE-860, Plurol Oleique CC 497, Caprol3GO, Caprol 10G10O, Caprol ET, and so on) Triglyceride (e.g., Captex300, 68-89 30-50 18-54 Captex 300 Low C6, Captex 350, Miglyol 810,Miglyol 812, and so on) Propylene glycol fatty acid ester 18-54 18-5468-89 30-50 18-54 (e.g., Lauroglycol 90, Captex 100, Capmul PG-8, CapmulPG-12, Capryol 90, Acconon E, and so on) Fatty acid or its salt (e.g.,oleic 68-89 30-50 acid, linoleic acid, lauric acid, octanoic acid,sodium caprate, sodium laurate, and so on) Edible oil (e.g., borage oil,68-89 30-50 30-50 peppermint oil, olive oil, coconut oil, omega-3 oil,and so on) Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s.

TABLE 2B Glyceryl fatty acid ester-comprising compositions Composition2B (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14Pregn-4-ene-3,20-dione 1-10  1-10 1-8 1-8 1-8 1-8 1-8 1-8 1-8 1-8 1-81-8 1-8 1-8 Glyceryl fatty acid ester (e.g., Capmul 30-85  30-49 30-4930-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 MCMC8, Capmul MCM, Capmul 808G, Imwitor 988, Maisine CC, and so on)Lipophilic Vitamin E or its derivative (e.g., 1-30 20-40 11-40 11-40additives TPGS, tocopherol acetate, tocotrienol, and so on) Polyglycerolfatty acid ester 41-60 30-40  3-20 (e.g., Caprol PGE-860, Plurol OleiqueCC 497, Caprol 3GO, Caprol 10G10O, Caprol ET, and so on) Triglyceride(e.g., Captex 300, 41-60 30-40 11-40 Captex 300 Low C6, Captex 350,Miglyol 810, Miglyol 812, and so on) Propylene glycol fatty acid ester 2-40 41-60 30-40 30-40 11-40 (e.g., Lauroglycol 90, Captex 100, CapmulPG-8, Capmul PG-12, Capryol 90, Acconon E, and so on) Fatty acid or itssalt (e.g., oleic 41-60 30-40 acid, linoleic acid, lauric acid, octanoicacid, sodium caprate, sodium laurate, and so on) Edible oil (e.g.,borage oil, 11-40 11-40 41-60 30-40 peppermint oil, olive oil, coconutoil, omega-3 oil, and so on) Other carrier ingredients q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

TABLE 2C Polyglycerol fatty acid ester-comprising compositionsComposition 2C (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14Pregn-4-ene-3,20-dione 1-8 1-6 1-6 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-51-5 1-5 Polyglycerol fatty acid ester (e.g.,  3-49 30-49 30-49 30-4930-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 CaprolPGE-860, Plurol Oleique CC 497, Caprol 3GO, Caprol 10G10O, Caprol ET,and so on) Lipophilic Vitamin E or its derivative (e.g., 41-68 30-4011-40 11-40 11-40 additives TPGS, tocopherol acetate, tocotrienol, andso on) Glyceryl fatty acid ester (e.g., 41-60 30-40 11-40 Capmul MCM C8,Capmul 808G, Imwitor 988, Maisine CC, and so on) Triglyceride (e.g.,Captex 300, 11-40 41-60 30-40 11-40 Captex 300 Low C6, Captex 350,Miglyol 810, Miglyol 812, and so on) Propylene glycol fatty acid ester41-60 30-40 30-40 (e.g., Lauroglycol 90, Captex 100, Capmul PG-8, CapmulPG-12, Capryol 90, Acconon E, and so on) Fatty acid or its salt (e.g.,oleic 41-60 30-40 30-40 acid, linoleic acid, lauric acid, octanoic acid,sodium caprate, sodium laurate, and so on) Edible oil (e.g., borage oil,11-40 11-40 41-60 30-40 peppermint oil, olive oil, coconut oil, omega-3oil, and so on) Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

TABLE 2D Triglyceride-comprising compositions Composition 2D (w/w %)Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Pregn-4-ene-3,20-dione  1-101-8 1-6 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 Triglyceride (e.g.,Captex 300, Captex 30-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 30-4930-49 30-49 30-49 30-49 30-49 300 Low C6, Captex 350, Miglyol 810,Migyol 812, and so on) Lipophilic Vitamin E or its derivative (e.g.,41-60 30-40 11-40 11-40 additives TPGS, tocopherol acetate, tocotrienol,and so on) Glyceryl fatty acid ester (e.g., 41-60 30-40 11-40 Capmul MCMC8, Capmul 808G, Imwitor 988, Maisine CC, and so on) Polyglycerol fattyacid ester 41-60 30-40 (e.g., Caprol PGE-860, Plurol Oleique CC 497,Caprol 3GO, Caprol 10G10O, Caprol ET, and so on) Propylene glycol fattyacid ester 11-40 11-40 41-60 30-40 30-40 11-40 (e.g., Lauroglycol 90,Captex 100, Capmul PG-8, Capmul PG-12, Capryol 90, Acconon E, and so on)Fatty acid or its salt (e.g., oleic 11-40 41-60 30-40 30-40 acid,linoleic acid, lauric acid, octanoic acid, sodium caprate, sodiumlaurate, and so on) Edible oil (e.g., borage oil, 11-40 41-60 30-40peppermint oil, olive oil, coconut oil, omega-3 oil, and so on) Othercarrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s.

TABLE 2E Propylene glycol fatty acid ester-comprising compositionsComposition 2E (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14Pregn-4-ene-3,20-dione  1-10 1-8 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-51-5 1-5 Propylene glycol fatty acid ester (e.g., 30-59  2-59 30-59 30-5930-59 30-59 30-59 30-59 30-59 30-59 30-59 30-59 30-59 30-59 Lauroglycol90, Captex 100, Capmu PG-8, Capmul PG-12, Capryol 90, Acconon E, and soon) Lipophilic Vitamin E or its derivative (e.g., 31-60 20-40 11-4011-40 11-40 additives TPGS, tocopherol acetate, tocotrienol, and so on)Glyceryl fatty acid ester (e.g., 11-48 31-60 20-40 11-40 Capmul MCM C8,Capmul 808G, Imwitor 988, Maisine CC, and so on) Polyglycerol fatty acidester 31-60 20-40 11-40 (e.g., Caprol PGE-860, Plurol Oleique CC 497,Caprol 3GO, Caprol 10G10O, Caprol ET, and so on) Triglyceride (e.g.,Captex 300, 11-40 31-60 20-40 20-40 Captex 300 Low C6, Captex 350,Miglyol 810, Miglyol 812, and so on) Fatty acid or its salt (e.g., oleic11-40 31-60 20-40 20-40 acid, linoleic acid, lauric acid, octanoic acid,sodium caprate, sodium laurate, and so on) Edible oil (e.g., borage oil,31-60 20-40 peppermint oil, olive oil, coconut oil, omega-3 oil, and soon) Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s.

TABLE 2F PEG glyceride of fatty acid ester-comprising compositionsComposition 2F (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14Pregn-4-ene-3,20-dione  1-10 1-8 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-51-5 1-5 PEG glyceride of fatty acid ester (e.g., 30-49 30-49  3-20 30-4930-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 30-49 Gelucire44/14, Gelucire 50/13, Acconon CC-6, Labrafil M1944CS, Labrasol, and soon) Lipophilic Vitamin E or its derivative (e.g., 41-69 20-40 21-4021-40 21-40 additives TPGS, tocopherol acetate, tocotrienol, and so on)Glyceryl fatty acid ester (e.g., 41-69 20-40 21-40 Capmul MCM C8, Capmul808G, Imwitor 988, Maisine CC, and so on) Polyglycerol fatty acid ester41-69 20-40 (e.g., Caprol PGE-860, Plurol Oleique CC 497, Caprol 3GO,Caprol 10G10O, Caprol ET, and so on) Triglyceride (e.g., Captex 300,21-40 41-69 20-40 Captex 300 Low C6, Captex 350, Miglyol 810, Miglyol812, and so on) Propylene glycol fatty acid ester 41-69 20-40 (e.g.,Lauroglycol 90, Captex 100, Capmul PG-8, Capmul PG-12, Capryol 90,Acconon E, and so on) Fatty acid or its salt (e.g., oleic 21-40 41-6920-40 acid, linoleic acid, lauric acid, octanoic acid, sodium caprate,sodium laurate, and so on) Edible oil (e.g., borage oil, 21-40 41-6920-40 peppermint oil, olive oil, coconut oil, omega-3 oil, and so on)Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s.

TABLE 2G Fatty acid or its salt-comprising compositions Composition 2G(w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14Pregn-4-ene-3,20-dione  1-10 1-8 1-8 1-6 1-6 1-6 1-6 1-6 1-6 1-6 1-6 1-61-6 1-6 Fatty acid or its salt (e.g., oleic acid, 30-59 30-59 30-5930-59 30-59 30-59 30-59 30-59 30-59 30-59 30-59 30-59 30-59 30-59linoleic acid, lauric acid, octanoic acid, sodium caprate, sodiumlaurate, and so on) Lipophilic Vitamin E or its derivative (e.g., 31-6020-40 20-40 11-40 11-40 additives TPGS, tocopherol acetate, tocotrienol,and so on) Glyceryl fatty acid ester (e.g., 11-40 31-60 20-40 Capmul MCMC8, Capmul 808G, Imwitor 988, Maisine CC, and so on) Polyglycerol fattyacid ester 31-60 20-40 11-40 (e.g., Caprol PGE-860, Plurol Oleique CC497, Caprol 3GO, Caprol 10G10O, Caprol ET, and so on) Triglyceride(e.g., Captex 300, 31-60 20-40 Captex 300 Low C6, Captex 350, Miglyol810, Miglyol 812, and so on) Propylene glycol fatty acid ester 11-4011-40 11-40 31-60 20-40 (e.g., Lauroglycol 90, Captex 100, Capmul PG-8,Capmul PG-12, Capryol 90, Acconon E, and so on) Edible oil (e.g., borageoil, 11-40 31-60 20-40 20-40 peppermint oil, olive oil, coconut oil,omega-3 oil, and so on) Other carrier ingredients q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

TABLE 2H Edible oil-comprising compositions Composition 2H (w/w %)Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Pregn-4-ene-3,20-dione  1-101-8 1-6 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 Edible oil (e.g.,borage oil, peppermint 30-59 30-59 30-59 30-59 30-59 30-59 30-59 30-5930-59 30-59 30-59 30-59 30-59 30-59 oil, olive oil, coconut oil, castoroil, omega-3 oil, and so on) Lipophilic Vitamin E or its derivative(e.g., 31-60 20-40 20-40 11-40 11-40 additives TPGS, tocopherol acetate,tocotrienol, and so on) Glyceryl fatty acid ester (e.g., 11-40 31-6020-40 Capmul MCM C8, Capmul 808G, Imwitor 988, Maisine CC, and so on)Polyglycerol fatty acid ester 31-60 20-40 11-40 (e.g., Caprol PGE-860,Plurol Oleique CC 497, Caprol 3GO, Caprol 10G10O, Caprol ET, and so on)Triglyceride (e.g., Captex 300, 31-60 20-40 Captex 300 Low C6, Captex350, Miglyol 810, Miglyol 812, and so on) Propylene glycol fatty acidester 11-40 11-40 11-40 31-60 20-40 11-40 (e.g., Lauroglycol 90, Captex100, Capmul PG-8, Capmul PG-12, Capryol 90, Acconon E, and so on) Fattyacid or its salt (e.g., oleic 31-60 20-40 20-40 acid, linoleic acid,lauric acid, octanoic acid, sodium caprate, sodium laurate, and so on)Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s.

Example 3—Pregn-4-ene-3,20-dione Compositions with Hydrophilic Additives

TABLE 3A Vitamin E or its derivative-comprising compositions Composition3A (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 Pregn-4-ene-3,20-dione 1-25 1-151-15  1-19 1-15 1-15  1-19 1-15  1-19 Vitamin E or its derivatives(e.g., TPGS, tocopherol, 15-35  40-70  40-70  40-70 40-70  40-70  40-7040-70  40-70 tocopherol acetate, and so on) Hydrophilic Polyoxylvegetable oil or glycerides (e.g., 5-25 5-25 5-25 additives KolliphorEL, Kolliphor RH40, Etocas 40, Croduret 60, Kolliphor HS 15, Etocas 5,Sterotex, Sterotex HM, Sterotex K, or a combination) PEG glyceride offatty acid esters (e.g., 5-25 20-50 5-25 5-25 Gelucire 44/14, Gelucire50/13, Acconon CC- 6, Labrafil M1944CS, Labrasol, and so on)Polyglycerol-10 fatty acid esters (e.g., 5-25 5-25 20-50 5-25glyceryl-10 mono-caprylate, glyceryl-10 mono-/di-caprylate, glyceryl-10di-caprylate, glyceryl-10 caprylate/caprate, and so on) Polysorbates(e.g., Tween 20, Tween 40, 5-25 5-25 20-50 Tween 80, and so on) Othercarrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

TABLE 3B Glyceryl fatty acid ester-comprising compositions Composition3B (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 Pregn-4-ene-3,20-dione  1-104-8 4-8 4-8 5-9 4-8 5-9 4-8 5-9 4-8 Glyceryl fatty acid esters (e.g.,Capmul 40-70 40-70 40-70 40-70 40-70 40-70 40-85 40-70 40-70 40-70 MCMC8, Capmul MCM, Capmul 808G, Imwitor 988, Maisine CC, and so on)Hydrophilic Polyoxyl vegetable oil or glycerides 20-50  5-25  5-25  3-25 5-25 additives (e.g., Kolliphor EL, Kolliphor RH40, Etocas 40, Croduret60, Kolliphor HS 15, Etocas 5, Sterotex, Sterotex HM, Sterotex K, or acombination) PEG glyceride of fatty acid esters  5-25  2-25  5-25 (e.g.,Gelucire 44/14, Gelucire 50/13, Acconon CC-6, Labrafil M1944CS,Labrasol, and so on) Polyglycerol-10 fatty acid esters (e.g., 20-50 5-25 glyceryl-10 mono-caprylate, glyceryl-10 mono-/di-caprylate,glyceryl-10 di- caprylate, glyceryl-10 caprylate/caprate, and so on)Polysorbates (e.g., Tween 20, Tween  3-25  5-25 40, Tween 80, and so on)Vitamin E esters (e.g., TPGS,  5-25  5-25 20-50  5-25 tocopherolacetate, and so on) Other carrier ingredients q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s.

TABLE 3C Polyglycerol fatty acid ester-comprising compositionsComposition 3C (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10Pregn-4-ene-3,20-dione 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5Polyglycerol fatty acid esters (e.g., Caprol 40-70 40-70 40-70 40-7040-70 40-70 40-70 40-70 40-70 40-70 PGE 860, Plurol Oleique CC 497,Caprol 3GO, Caprol 10G10O, Caprol ET, and so on) Hydrophilic Polyoxylvegetable oil or glycerides (e.g., 20-50  5-25  5-25  5-25 additivesKolliphor EL, Kolliphor RH40, Etocas 40, Croduret 60, Kolliphor HS 15,Etocas 5, Sterotex, Sterotex HM, Sterotex K, or a combination) PEGglyceride of fatty acid esters (e.g.,  5-25 20-50  5-25 Gelucire 44/14,Gelucire 50/13, Acconon CC-6, Labrafil M1944CS, Labrasol, and so on)Polyglycerol-10 fatty acid esters (e.g., 20-50  5-25 glyceryl-10mono-caprylate, glyceryl-10 mono-/di-caprylate, glyceryl-10 di-caprylate, glyceryl-10 caprylate/caprate, and so on) Polysorbates (e.g.,Tween 20, Tween 40, 20-50  5-25 Tween 80, and so on) Vitamin E esters(e.g., TPGS, tocopherol  5-25  5-25 20-50  5-25 acetate, and so on)Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

TABLE 3D Triglyceride-comprising compositions Composition 3D (w/w %)Ingredient 1 2 3 4 5 6 7 8 9 10 Pregn-4-ene-3,20-dione 1-5 1-5 1-5 1-51-5 1-5 1-5 1-5 1-5 1-5 Triglycerides (e.g., Captex 300, Captex 30040-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70 Low C6,Captex 350, Miglyol 810, Miglyol 812, and so on) Hydrophilic Polyoxylvegetable oil or glycerides (e.g., 20-50  5-25  5-25 additives KolliphorEL, Kolliphor RH40, Etocas 40, Croduret 60, Kolliphor HS 15, Etocas 5,Sterotex, Sterotex HM, Sterotex K, or a combination) PEG glyceride offatty acid esters (e.g.,  5-25 20-50  5-25 Gelucire 44/14, Gelucire50/13, Acconon CC-6, Labrafil M1944CS, Labrasol, and so on)Polyglycerol-10 fatty acid esters (e.g., 20-50  5-25 glyceryl-10mono-caprylate, glyceryl-10 mono-/di-caprylate, glyceryl-10 di-caprylate, glyceryl-10 caprylate/caprate, and so on) Polysorbates (e.g.,Tween 20, Tween 40, 20-50  5-25 Tween 80, and so on) Vitamin E esters(e.g., TPGS, tocopherol  5-25  5-25  5-25 20-50  5-25 acetate, and soon) Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s.

TABLE 3E Propylene glycol fatty acid ester-comprising compositionsComposition 3E (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10Pregn-4-ene-3,20-dione 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 Propyleneglycol fatty acid esters (e.g., Lauroglycol 90, Captex 100, Capmul PG-8,40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70 CapmulPG-12, Capryol 90, Acconon E, and so on) Hydrophilic Polyoxyl vegetableoil or glycerides (e.g., 20-50  5-25  5-25 additives Kolliphor EL,Kolliphor RH40, Etocas 40, Croduret 60, Kolliphor HS 15, Etocas 5,Sterotex, Sterotex HM, Sterotex K, or a combination) PEG glyceride offatty acid esters (e.g.,  5-25 20-50  5-25 Gelucire 44/14, Gelucire50/13, Acconon CC-6, Labrafil M1944CS, Labrasol, and so on)Polyglycerol-10 fatty acid esters (e.g., 20-50  5-25 glyceryl-10mono-caprylate, glyceryl-10 mono-/di-caprylate, glyceryl-10 di-caprylate, glyceryl-10 caprylate/caprate, and so on) Polysorbates (e.g.,Tween 20, Tween 40, 20-50  5-25 Tween 80, and so on) Vitamin E esters(e.g., TPGS, tocopherol  5-25  5-25  5-25 20-50  5-25 acetate, and soon) Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s.

TABLE 3F PEG glyceride of fatty acid ester-comprising compositionsComposition 3F (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10Pregn-4-ene-3,20-dione 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 PEGglyceride of fatty acid esters (e.g., Gelucire 40-70 40-70 40-70 40-7040-70 40-70 40-70 40-70 40-70 40-70 44/14 Gelucire 50/13, Acconon CC-6,Labrafil M1944CS, Labrasol, and so on) Hydrophilic Polyoxyl vegetableoil or glycerides (e.g., 20-50  5-25  5-25  5-25 additives Kolliphor EL,Kolliphor RH40, Etocas 40, Croduret 60, Kolliphor HS 15, Etocas 5,Sterotex, Sterotex HM, Sterotex K, or a combination) Polyglycerol-10fatty acid esters (e.g.,  5-25 20-50  5-25  5-25 glyceryl-10mono-caprylate, glyceryl-10 mono-/di-caprylate, glyceryl-10 di-caprylate, glyceryl-10 caprylate/caprate, and so on) Polysorbates (e.g.,Tween 20, Tween 40,  5-25 20-50  5-25  5-25 Tween 80, and so on) VitaminE esters (e.g., TPGS, tocopherol  5-25  5-25 20-50  5-25 acetate, and soon) Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s.

TABLE 3G Fatty acid or its salt-comprising compositions Composition 3G(w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 Pregn-4-ene-3,20-dione 1-5 1-51-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 Fatty acid or its salts (e.g., oleicacid, 40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70linoleic acid, lauric acid, octanoic acid, sodium caprate, sodiumlaurate, and so on) Hydrophilic Polyoxyl vegetable oil or glycerides20-50  5-25  5-25  5-25  5-25 additives (e.g., Kolliphor EL, KolliphorRH40, Etocas 40, Croduret 60, Kolliphor HS 15, Etocas 5, Sterotex,Sterotex HM, Sterotex K, or a combination) PEG glyceride of fatty acidesters  5-25 20-50  5-25 (e.g., Gelucire 44/14, Gelucire 50/13, AccononCC-6, Labrafil M1944CS, Labrasol, and so on) Polyglycerol-10 fatty acidesters (e.g., 20-50  5-25 glyceryl-10 mono-caprylate, glyceryl- 10mono-/di-caprylate, glyceryl-10 di- caprylate, glyceryl-10caprylate/caprate, and so on) Polysorbates (e.g., Tween 20, Tween 20-50 5-25 40, Tween 80, and so on) Vitamin E esters (e.g., TPGS,  5-25 20-50 5-25 tocopherol acetate, and so on) Other carrier ingredients q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

TABLE 3H Edible oil-comprising compositions Composition 3H (w/w %)Ingredient 1 2 3 4 5 6 7 8 9 10 Pregn-4-ene-3,20-dione 1-4 1-4 1-4 1-41-4 1-4 1-4 1-4 1-4 1-4 Edible oils (e.g., borage oil, peppermint oil,olive oil, 40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70 40-70coconut oil, castor oil, omega-3 oil, and so on) Hydrophilic Polyoxylvegetable oil or glycerides (e.g., 20-50  5-25  5-25  5-25 additivesKolliphor EL, Kolliphor RH40, Etocas 40, Croduret 60, Kolliphor HS 15,Etocas 5, Sterotex, Sterotex HM, Sterotex K, or a combination) PEGglyceride of fatty acid esters (e.g.,  5-25 20-50  5-25 Gelucire 44/14,Gelucire 50/13, Acconon CC-6, Labrafil M1944CS, Labrasol, and so on)Polyglycerol-10 fatty acid esters (e.g., 20-50  5-25 glyceryl-10mono-caprylate, glyceryl-10 mono-/di-caprylate, glyceryl-10 di-caprylate, glyceryl-10 caprylate/caprate, and so on) Polysorbates (e.g.,Tween 20, Tween 40, 20-50  5-25 Tween 80, and so on) Vitamin E esters(e.g., TPGS, tocopherol  5-25  5-25 20-50  5-25 acetate, and so on)Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s.

Example 4—Pregn-4-ene-3,20-dione Compositions

TABLE 4A Specific Examples of Vit-E-comprising CompositionsVit-E-comprising Composition 4A (w/w %) Ingredient 1 2 3 4 5 6 7 8Pregn-4-ene-3,20-dione 10-20 20-25 1-8  1-10 1-10 1-10 1-10  1-10Alpha-Tocopherol 80-90 20-25  2-22 20-45 10-22  4-25 10-22  10-22Glyceryl caprylate/caprate 40-65 20-45 (e.g., Capmul MCM, Capmul 708G)Glyceryl monocaprylate 30-45 30-85  20-45  (e.g., Capmul MCM C8)Glyceryl monolinoleate 20-45  20-45 (e.g., Maisine) Octanoic acidPeppermint oil Coconut oil Lipophilic Span80 additives† Lauroglycol 3-6 5-25 5-25 2-15 5-25 Labraphil M2125 CS Hydrophilic TPGS 10-30 25-50 5-30 5-25 5-50 5-25 25-50 additives† Caprol PGE-860 Labrasol Tween80Kolliphor EL Kolliphor RH40 Other carrier ingredients q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. Crystalline form of No Yes No No No No No NoPregn-4-ene-3,20-dione Vit-E-comprising Composition 4A (w/w %)Ingredient 9 10 11 12 13 14 15 Pregn-4-ene-3,20-dione 1-10  1-12 1-12 1-12 1-12  1-10 1-10 Alpha-Tocopherol 10-22  10-22 10-22  10-20 10-20 10-20 10-20  Glyceryl caprylate/caprate (e.g., Capmul MCM, Capmul 708G)Glyceryl monocaprylate (e.g., Capmul MCM C8) Glyceryl monolinoleate(e.g., Maisine) Octanoic acid 20-45  20-45 Peppermint oil 20-70  20-70Coconut oil 20-70  20-70 Lipophilic Span80 additives† Lauroglycol 5-255-25 5-25 5-25 Labraphil M2125 CS Hydrophilic TPGS 5-25 25-50 5-25 25-505-25 25-50 5-25 additives† Caprol PGE-860 Labrasol Tween80 Kolliphor ELKolliphor RH40 Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s.q.s. Crystalline form of No No No No No No No Pregn-4-ene-3,20-dione †Lipophilic or hydrophilic additives can be selected at least one or acombination of the ingredients shown in the table. Hereafter it appliesto all examples.

TABLE 4B Specific examples of fatty acid or its salt-comprisingCompositions Fatty acid or its salt-comprising Composition 4B (w/w %)Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Pregn-4-ene-3,20-dione10-15 1-8 1-8  1-12 1-12  1-10 1-10  1-10 1-10  1-10 1-10  1-10 1-10 1-10 1-10 Octanoic acid 85-90 30-50 30-50 30-50 30-50  30-50 30-50 30-50 30-50  30-50 30-50  30-50 30-50  30-50 30-50  Alpha-Tocopherol10-22 10-22  Glyceryl caprylate/caprate 10-30 20-30  (e.g., Capmul MCM,Capmul 708G) Glyceryl monocaprylate 10-30 20-30  (e.g., Capmul MCM C8)Glyceryl monolinoleate 10-30 20-30  (e.g., Maisine) Peppermint oil 10-3020-30  Coconut oil 10-30 20-30  Lipophilic Span80  5-25 5-25 5-25 5-255-25 5-25 5-25 additives Lauroglycol Labraphil M2125 CS Hydrophilic TPGS25-50  5-25 25-50 5-25 25-50 5-25 25-50 5-25 25-50 5-25 25-50 5-25 25-505-25 additives Caprol PGE-860 Labrasol Tween80 Kolliphor EL KolliphorRH40 Other carrier Ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. Crystalline form of Yes No No No NoNo No No No No No No No No No Pregn-4-ene-3,20-dione

TABLE 4C Specific examples of glyceryl fatty acid ester-comprisingCompositions Glyceryl fatty acid ester-comprising Composition 4C (w/w %)Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 Pregn-4-ene-3,20-dione 5-10  5-105-10  1-10 1-10 1-10 1-10 1-6 1-6 1-6 1-6 1-6 Glyceryl caprylate/caprate50-85  50-70  30-50  30-50 30-50 (e.g., Capmul MCM, Capmul 708G)Glyceryl monocaprylate 90-95 40-70 40-70  30-50  30-50 30-50 30-50(e.g., Capmul MCM C8) Alpha-Tocopherol 10-22 10-22  10-22  10-22 Octanoic acid 20-30 20-30 Glyceryl monolinoleate 20-30 (e.g., Maisine)Peppermint oil 20-35 Coconut oil 20-35 Lipophilic Span80 1-10 5-25 5-255-25  5-25  5-25 additives Lauroglycol Labraphil M2125 CS HydrophilicTPGS 5-15 20-50 0-10  5-25 5-25 5-25 5-25 25-50 25-50  5-25  5-25 25-50additives Caprol PGE-860 Labrasol Tween80 Kolliphor EL Kolliphor RH40Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. Crystalline form of Yes No Yes No No No Yes No No No YesNo Pregn-4-ene-3,20-dione

TABLE 4D Specific examples of PEG glyceride of fatty acidester-comprising Compositions PEG glyceride of fatty acid estercomprising Compositon 4D (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 11 1213 14 15 Pregn-4-ene-3,20-dione 1-5 1-5 1-5 1-6 1-6 1-8 1-8 1-5 1-5 1-51-5 1-5 1-5 1-5 1-5 PEG-6 mono/di-linoleate 95-99 50-70 40-70 30-5030-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 (e.g.,Labraphil M2125 CS) Octanoic acid 25-40 10-25 Alpha-Tocopherol 10-2210-22 Glyceryl caprylate/caprate 20-30 (e.g., Capmul MCM, Capmul 708G)Glyceryl monocaprylate 20-30 (e.g., Capmul MCM C8) Glycerylmonolinoleate 20-30 20-30 (e.g., Maisine) Peppermint oil 20-30 20-30Coconut oil 20-30 20-30 Lipophilic Span80  5-25  5-25  5-25  5-25  5-25 5-25  5-25 additives Lauroglycol Hydrophilic TPGS 20-50  5-25 25-50 5-25 25-50  5-25 25-50  5-25 25-50  5-25 25-50  5-25 25-50  5-25additives Caprol PGE-860 Labrasol Tween80 Kolliphor EL Kolliphor RH40Other carrier Ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. Crystalline form of Yes Yes Yes No No NoNo Yes No Yes Yes No No Yes Yes Pregn-4-ene-3,20-dione

TABLE 4E Specific examples of polyglycerol fatty acid ester-comprisingCompositions Polyglycerol fatty acid ester-comprising Composition 4E(w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Pregn-4-ene-3,20-dione 1-4 1-4 1-4 1-6 1-6 1-6 1-6 1-5 1-5 1-5 1-5 1-51-5 1-5 1-5 Polyglyceryl-10 mono/di- 95-99 50-70 40-70 30-50 30-50 30-5030-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 oleate (e.g.,Caprol PGE- 860) Octanoic acid 25-40 10-25 Alpha-Tocopherol 10-22 10-22Glyceryl caprylate/caprate 20-30 (e.g., Capmul MCM, Capmul 708G)Glyceryl monocaprylate 20-30 (e.g., Capmul MCM C8) Glycerylmonolinoleate 20-30 20-30 (e.g., Maisine) Peppermint oil 20-30 20-30Coconut oil 20-30 20-30 Lipophilic Span80  5-25  5-25  5-25  5-25  5-25 5-25  5-25 additives Lauroglycol Labraphil M2125 CS Hydrophilic TPGS20-50  5-25 25-50  5-25 25-50  5-25 25-50  5-25 25-50  5-25 25-50  5-2520-50 25-50 additives Labrasol Tween80 Kolliphor EL Kolliphor RH40 Othercarrier Ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. Crystalline form of Yes Yes Yes No No No No YesYes Yes Yes No No Yes Yes Pregn-4-ene-3,20-dione

TABLE 4F Specific examples of triglyceride-comprising CompositionsPolyglycerol fatty acid ester-comprising Composition 4F (w/w %)Ingredient 1 2 3 4 5 6 7 8 9 12 13 14 15 16 17 Pregn-4-ene-3,20-dione1-4 1-4 1-4 1-6 1-6 1-6 1-6 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5Caprylic/Capric 95-99 50-70 40-70 30-50 30-50 30-50 30-50 30-50 30-5030-50 30-50 30-50 30-50 30-50 30-50 triglyceride (e.g., Captex 300)Octanoic acid 25-40 10-25 Alpha-Tocopherol 10-22 10-22 Glycerylcaprylate/caprate 20-30 (e.g., Capmul MCM, Capmul 708G) Glycerylmonocaprylate 20-30 (e.g., Capmul MCM C8) Glyceryl monolinoleate 20-3020-30 (e.g., Maisine) Peppermint oil 20-30 20-30 Coconut oil 20-30 20-30Lipophilic Span80  5-25  5-25  5-25  5-25  5-25  5-25  5-25 additivesLauroglycol Labraphil M2125 CS Hydrophilic TPGS 20-50  5-25 25-50  5-2525-50  5-25 25-50  5-25 25-50  5-25 25-50  5-25 25-50  5-25 additivesCaprol PGE-860 Labrasol Tween80 Kolliphor EL Kolliphor RH40 Othercarrier ingredients q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. Crystalline form of Yes Yes Yes No No No No YesYes Yes Yes No No Yes Yes Pregn-4-ene-3,20-dione

TABLE 4G Specific Examples of propylene glycol fatty acidester-comprising Compositions Polyglycerol fatty acid ester-comprisingComposition 4G (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Pregn-4-ene-3,20-dione  5-10 1-8 1-8  1-10 1-10  1-10 1-10 1-8 1-8 1-81-8 1-8 1-8 1-8 1-8 Propylene glycol 90-95 50-70 40-70 30-50 30-50 30-50 30-50  30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50monocaprylate (e.g., Capmul PG-8) Octanoic acid 25-40 10-25 Alpha-Tocopherol 10-22 10-22  Glyceryl caprylate/caprate 20-30 (e.g.,Capmul MCM, Capmul 708G) Glyceryl monocaprylate 20-30 (e.g., Capmul MCMC8) Glyceryl monolinoleate 20-30 20-30 (e.g., Maisine) Peppermint oil20-30 20-30 Coconut oil 20-30 20-30 Lipophilic Span80  5-25 5-25 5-25 5-25  5-25  5-25  5-25 additives Lauroglycol Labraphil M2125 CSHydrophilic TPGS 20-50  5-25 25-50 5-25 25-50 5-25 25-50  5-25 25-50 5-25 25-50  5-25 25-50  5-25 additives Caprol PGE-860 Labrasol Tween80Kolliphor EL Kolliphor RH40 Other carrier Ingredients q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Crystallineform of No No Yes No No No No No No No Yes No No No YesPregn-4-ene-3,20-dione

TABLE 4H Specific Examples of edible oil-comprising Compositions Edibleoil-comprising Composition 4H (w/w %) Ingredient 1 2 3 4 5 6 7 8 9 10 1112 13 14 15 16 Pregn-4-ene-3,20-dione  5-10 1-8 1-8  1-10 1-10  1-101-10 3-6 1-6 1-6 1-8 1-6 1-6 1-6 1-6 1-6 Peppermint oil 90-95 40-8030-60 20-50 20-50  20-50 20-50  Coconut oil 94-97 40-80 30-60 20-5020-50 20-50 20-50 20-50 20-50 Alpha-Tocopherol 10-22 10-22 Glycerylcaprylate/caprate 20-40 (e.g., Capmul MCM, Capmul 708G) Glycerylmonocaprylate 20-40  20-40  5-20 (e.g., Capmul MCM C8) Glycerylmonolinoleate 20-40 20-40 (e.g., Maisine) Propylene glycol monocaprylate(e.g., 20-40  20-40 Capmul PG-8) Lipophilic Span80  5-25 5-25 5-25  5-25 5-25  5-25  5-25 additives Labraphil M2125 CS Lauroglycol HydrophilicTPGS 25-50  5-25 25-50 5-25 25-50 5-25  5-25 25-50  5-25 25-50  5-2525-50 25-50  5-25 additives Caprol PGE-860 Labrasol Tween80 Kolliphor ELKolliphor RH40 Other carrier Ingredients q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Crystalline form of NoNo Yes No No No No No No No No No No No No No Pregn-4-ene-3,20-dione

Example 5—Pregn-4-ene-3,20-dione Compositions

In one aspect, the examples described in the following pharmaceuticalcomposition tables can be formulated with or without at least one ormore polymeric release modifiers. In yet another aspect, these examplescan be formulated with or without at least one or more 5-alpha-reductaseenhancers, wherein the carriers or its components in the formulationsherein are surprisingly found to promote conversion ofpregn-4-ene-3,20-dione, possibly serving as 5α-reductase enhancers. Forexample, the carriers comprising alpha-tocopherol, glycerylmonocaprylate, and a combination thereof can increase conversion ofpregn-4-ene-3,20-dione to its GABA_(A) receptor allosteric metabolites(e.g., 3α-OH-5α-pregnan-20-one and/or 3α-OH-5β-pregnan-20-one).5α-reductase enhancers promote the conversion of pregn-4-ene-3,20-dioneinto its metabolites (e.g., 3α-OH-5α-pregnan-20-one and/or3α-OH-5β-pregnan-20-one). These pharmaceutical compositions comprisingnon crystalline or partially or fully solubilized pregn-4-ene-3,20-dionedescribed herein can provide pharmaceutically effective levels of theseGABA_(A) receptor agonists for treatment of a CNS disorder. Thesepharmaceutical compositions were prepared using standard techniquescommonly used in the pharmaceutical field.

TABLE 5 Oral compositions comprising Non-crystalline forms ofpregn-4-ene-3,20-dione Composition (w/w %) Component 5-1 5-2 5-3 5-4 5-55-6 5-7 5-8 5-9 5-10 5-11 5-12 5-13 5-14 5-15* Pregn-4-ene-3,20-dione6-8 6-9 6-9  3-10 6-9 6-8 5-8  3-10  7-10 4-7 6-9 20-25  7-10 4-6 35-42Glyceryl monocaprylate 80-85 43-48 43-48 60-68 43-48 43-48 43-48 30-40(e.g., Capmul MCM C8) Edible oil (e.g., Peanut oil) 65-85 45-50Propylene Glycol 43-48 38-43 monolaurate (e.g., Lauroglycol) PropyleneGlycol 2-5 55-60 13-18 Monocaprylate (e.g., Capmul PG-8) Lecithin 0-5Alpha-tocopherol 3-5 18-22 18-22 18-22 18-22 18-22 2-5 18-22 2-5 18-2215-25 18-22 2-5 Peppennint oil 28-35 42-50 TPGS  6-10 22-28 13-18 18-22Polyethylene glycol castor oil (e.g., Kolliphor EL, 4-8 22-28 22-28 4-813-18 13-18 3-8 42-50 28-35 22-28 13-18 10-15  7-11 22-28 KolliphorRH40) Sodium lauryl sulfate 3-8  5-10 Polyglyceryl-10 mono/di-  6-10oleate (e.g., Caprol PGE- 860) Glyceryl distearate 3-6 Additives q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 *Anoral composition with a micronized crystalline form ofpregn-4-ene-3,20-dione

As shown in the above examples, the compositions can provide fullysolubilized or non-crystalline forms of pregn-4-ene-3,20-dione. The oralcompositions of the present disclosure can be formulated to provide %release rates that can yield enhanced therapeutic effects of the GABAreceptor modulating metabolites of Pregn-4-ene-3,20-dione. In oneexample, the compositions or oral dosage forms (Composition 5-8 and5-12) were formulated to have a release rate in vitro when measuredusing a USP Type-I dissolution apparatus in 900 mL of deionized waterwith 2.0% (w/v) of SLS at 100 rpm at 37° C. FIG. 2 shows that thepresent oral compositions or dosage forms (e.g., Composition 5-8 and5-12) can release at least one of greater than about 50% of thepregn-4-ene-3,20-dione after 15 minutes, greater than about 75% of thepregn-4-ene-3,20-dione after 30 minutes, greater than about 90% of thepregn-4-ene-3,20-dione after 60 minutes, and greater than 50% of thepregn-4-ene-3,20-dione in 4 hours when measured using a USP Type Idissolution apparatus in 900 mL of deionized water with 2.0% (w/v) ofSLS at 100 rpm at 37° C. Surprisingly, it was found that the presentoral compositions (e.g., Composition 5-8 and 5-12) can release greaterthan about 30% more of pregn-4-ene-3,20-dione after 15 minutes ascompared to the % release from a micronized administration (e.g.,Composition 5-15).

In another example, the compositions or oral dosage forms (Composition5-4, 5-8, and 5-12) were formulated to have a release rate in vitro whenmeasured using a USP Type-II dissolution apparatus in 900 mL ofdeionized water with 0.25% (w/v) of SLS at 75 rpm at 37° C. FIG. 3 showsthat the present oral compositions or dosage forms (e.g., Composition5-4, 5-8, and 5-12) can release at least one of greater than about 50%of the pregn-4-ene-3,20-dione after 20 minutes, greater than about 75%of the pregn-4-ene-3,20-dione after 30 minutes, greater than about 90%of the pregn-4-ene-3,20-dione after 60 minutes, and greater than 50% ofthe pregn-4-ene-3,20-dione in 4 hours when measured using a USP Type-IIdissolution apparatus in 900 mL of deionized water with 0.25% (w/v) ofSLS at 75 rpm at 37° C.

Example 6—Pregn-4-ene-3,20-dione Compositions

TABLE 6 Oral compositions comprising pregn-4-ene-3,20-dione Composition(w/w %) Component 6-1 6-2 6-3 6-4 6-5 6-6 6-7 6-8 6-9 6-10 6-11 6-126-13 6-14 6-15 Pregn-4-ene-3,20-dione 7.6 7.5 7.0 9.0 7.5 7.0 6.0 4.38.5 5.5 6.5 23.5 8.0 5.0 40.0 Glyceryl 82.9 45.5 46.0 63.7 46.0 46.046.0 35.0 monocaprylate (e.g., Capmul MCM C8) Edible oil (e.g., 84.649.6 Peanut oil) Propylene Glycol 2.0 40.0 40.0 monolaurate (e.g.,Lauroglycol) Propylene Glycol 57.5 16.0 Monocaprylate (e.g., CapmulPG-8) Lecithin 0.4 Alpha-tocopherol 4.6 20.0 20.5 20.5 21.0 21.0 2.521.0 4.0 21.0 20.5 21.0 4.0 Peppermint oil 30.0 45.0 TPGS 9.0 25.5 16.021.0 Sodium lauryl 4.7 6.5 sulfate PEG Castor Oil (e.g., 4.9 25.0 26.56.8 16.5 17.0 4.7 47.2 30.5 25.0 15.0 10.5 9.0 25.0 Kolliphor EL,Kolliphor RH40) Polyglyceryl-10 9.0 mono/di-oleate (e.g., CaprolPGE-860) Glyceryl distearate 4.0 Additives q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Total 100 100 100 100 100100 100 100 100 100 100 100 100 100 100 % w/w Ratio of 1.7 0.4 0.4 0.40.4 0.3 N/A 1.7 0.4 1.4 0.3 1.1 0.4 1.3 N/A Pregn-4-ene-3,20-dione/alpha- tocopherol % w/w Ratio of 0.1 0.2 0.2 0.1 0.2 0.2 N/A 0.1N/A N/A N/A 0.7 N/A N/A N/A Pregn-4-ene-3,20- dione/glycerylmonocaprylate % w/w Ratio of 0.9 0.8 0.8 3.0 0.8 0.8 N/A 0.1 0.7 0.1 1.41.2 0.8 0.1 N/A alpha- tocopherol/hydrophilic ingredient % w/w Ratio ofglyceryl 16.9 1.8 1.8 9.4 2.8 2.7 N/A 1.0 N/A N/A N/A 2.1 N/A N/A N/Amonocaprylate/ hydrophilic ingredient

As shown in the Table 6, the oral compositions or dosage forms canprovide a ratio of pregn-4-ene-3,20-dione to alpha-tocopherol from about0.3 to 2.0, such as about 0.3, about 0.4, about 0.5, about 0.6, about0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3,about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, andabout 2.0.

In one example, the oral compositions or dosage forms can provide aratio of Pregn-4-ene-3,20-dione to glyceryl monocaprylate less thanabout 0.7, such as about 0.7, about 0.6, about 0.5, about 0.4, about0.3, about 0.2, about 0.19, about 0.18, about 0.17, about 0.16, about0.15, about 0.14, about 0.13, about 0.12, about 0.11, about 0.10, about0.09, and less than about 0.09.

In another example, the oral compositions or dosage forms can provide aratio of alpha-tocopherol to a hydrophilic ingredient from about 0.05 to4.0, such as about 0.05, about 0.1, about 0.3, about 0.5, about 0.7,about 0.9, about 1.1, about 1.3, about 1.4, about 1.7, about 2.0, about2.3, about 2.6, about 2.9, about 3.2, about 3.5, and about 4.0.

In a further example, the oral compositions or dosage forms can providea ratio of glyceryl monocaprylate to a hydrophilic ingredient from about1 to 20 or about 1 to 10, such as about 1, about 2, about 3, about 4,about 5, about 6, about 7, about 8, about 9, and about 10. In anotherexample, the ratio of glyceryl monocaprylate to a hydrophilic ingredientcan be from less than about 2.5, such as about 2.4, about 2.3, about2.2, about 2.1, about 2.0, about 1.9, about 1.8, about 1.7, about 1.6,about 1.5, about 1.4, about 1.3, about 1.2, about 1.1, about 1.0, andless than about 1.0.

Example 7—Pregn-4-ene-3,20-dione Drink Compositions

TABLE 7A Drink compositions comprising pregn-4-ene-3,20-dioneComposition 7A (w/w %) Component* I II III IV V Pregn-4-ene-3,20-dione0.067-1    0.067-1    0.067-1   0.067-1   0.067-1   Vitamin E or itsderivatives (e.g., TPGS, 0.067-3.33 0.067-3.33 tocopherol, tocopherolacetate, tocotrienol, or a combination) Lipophilic additive (e.g.,glyceryl 0.33-5.67 0.067-4.67 0.067-4.67 monocaprylate, glyceryl monoand dicaprylocaprate, propylene glycol monolaurate, propylene glycolmonocaprylate, sorbitan monolaurate, glyceryl monolinoleate, sorbitanmonooleate, linoleoyl polyoxyl-6 glycerides, polyglyceryl 3-oleate,oleoyl polyoxyl-6 glyceride, peppermint oil, caprylic acid, oleic acid,castor oil, linoleic acid, and a combination thereof) Hydrophilicadditive (s) (e.g., PEG-35 castor 0.33-5.67  0.33-6.00  0.33-6.00 0.33-6.00 oil, PEG-40 hydrogenated castor oil, polysorbate 80,polysorbate 20, polyglyceryl- 10 monooleate, polyglyceryl-10 dioleate,polyglyceryl-10 monocaprylate, polyglyceryl-10 dicaprylate, glyceryl-10caprylate/caprate, glyceryl-10 monocaprate, caprylocaproyl polyoxyl-8glyceride, tocopherol polyethylene glycol succinate, lauroyl PEG-32glyceride, and a combination thereof) Purified Water q.s to q.s to q.sto q.s to q.s to 100% 100% 100% 100% 100% *Components in the drinkcompositions can comprise other carrier ingredients comprising at least,one of flavoring agents, sweeteners, antimicrobial preservatives,antioxidants, and edible fat.

TABLE 7B Drink compositions comprising pregn-4-ene-3,20-dioneComposition 7B (% w/w) Component* I II III IV V Pregn-4-ene-3,20-dione0.27 0.47 0.43 0.29 0.47 Glyceryl monocaprylate 2.07 3.13 3.00 3.07 3.07Polyoxyl 40 3.67 1.67 1.67 3.15 1.77 hydrogenated castor oilAlpha-Tocopherol 0.67 1.33 0.93 0.17 1.37 Propylene glycol 0.63Monolaurate Purified Water q.s. to q.s. to q.s. to q.s. to q.s. to 100%100% 100% 100% 100% *Components in the drink compositions can compriseoptional carrier ingredients comprising at least, one of flavoringagents, sweeteners, antimicrobial preservatives, antioxidants, andedible fat.

TABLE 7C Drink compositions comprising pregn-4-ene-3,20-dioneComposition 7C (% w/w) Component* I II III IV Pregn-4-ene-3,20-dione0.60 0.51 0.30 0.63 Glyceryl monocaprylate 4.25 5.53 4.13 Polyoxyl 40hydrogenated 0.45 0.33 2.77 castor oil Alpha-Tocopherol 1.37 0.31 0.931.33 TPGS 0.50 Propylene glycol 0.90 Monolaurate Oleoyl polyoxyl-6 1.17glycerides Sorbitan Monooleate 0.60 Purified Water q.s. to q.s. to q.s.to q.s. to 100% 100% 100% 100% *Components in the drink compositions cancomprise optional carrier ingredients comprising at least one offlavoring agents, sweeteners, antimicrobial preservatives, antioxidants,and edible fat.

Example 8—Clinical Study Example I for PK Measure

Assessment of the present dosage forms of Pregn-4-ene-3,20-dionecompositions relative to prior art composition in a single dose can beconducted based on actual results and/or simulated data from clinicalstudies reported in the literature and studies conducted by Applicant asa single-dose crossover design, wherein volunteers were randomized tosix different treatments (Composition A, B, C, E: 200 mg, andComposition D and F: 95 mg) under fasting conditions. The pharmaceuticalcompositions comprising Pregn-4-ene-3,20-dione for this investigationare depicted in Table 7. The study population consisted of twelve (12)healthy non-smoking non-hysterectomized postmenopausal women 45 to 65years of age with a BMI of 18-32 kg/m².

Venous blood samples were collected into evacuated vacuum collectiontubes comprising sodium heparin as anticoagulant for the concentrationmeasurement of plasma pregn-4-ene-3,20-dione and its metabolites atpre-dose (time −1.0, −0.5, and 0.0), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8,10, 12, 18, and 24 hours after dosing. Time 0 samples were collectedwithin 30 minutes prior to the first study drug administration of eachtreatment period. Concentrations of pregn-4-ene-3,20-dione,3α-OH-5α-pregnan-20-one, 3α-OH-5β-pregnan-20-one,3β-OH-5α-pregnan-20-one, and 3β-OH-5β-pregnan-20-one were measured usinga chromatography combined mass spectrometry method (e.g., LC-MS/MS orGC-MS).

TABLE 8A Composition % w/w Component Comp. A Comp. B Comp. C Comp. DComp. E Comp. F Pregn-4-ene-3,20-dione 40.0 30.0 23.5  4.3  9.0 23.5Edible Oil (e.g., peanut oil) 49.6 — — — — — Caprylic/capric glycerides— 65.9 — — — — (e.g., Capmul 708G, Capmul MCM) Glyceryl monocaprylate —— — 46.0 63.7 35.0 (e.g., Capmul MCM C8) Alpha-tocopherol — — —  2.520.5 20.5 Sodium lauryl sulfate — —  5.9 — —  6.5 Release modulator(e.g., — — 57.7 — — — Hydroxypropyl methylcellulose) Polysorbate 80 — — 1.0 — — — Lecithin  0.4  1.1 — — — — Lauroyl polyoxyl-32 —  3.0 — — — —glycerides (e.g., Gelucire 44/14) Polyoxyl castor oil (e.g., — — — 47.2 6.8 10.5 Kolliphor EL, Kolliphor RH40) Glyceryl distearate — — — — — 4.0 Other carrier ingredients q.s. q.s. q.s. q.s. q.s. q.s.

TABLE 8B PK Parameters Post Single Dose Administration of CompositionsPK Values PK Parameters Comp. A Comp. B Comp. C Comp. D Comp. E Comp. FPregn-4-ene-3,20-dione C_(max), mean (ng/ml) 3.0 3.3 1.0 6.2 7.5 4.7T_(max), mean (hr) 1.5 1.5 4.5 1.5 1.5 2.0 3α-OH-5β-pregnan-20-oneC_(max), mean (ng/ml) 10.0  10.5  2.1 26.7  31.8  20.4  >11.0 ng/ml NoNo No Yes Yes Yes <90.0 ng/ml Yes Yes Yes Yes Yes Yes3α-OH-5α-pregnan-20-one C_(max), mean (ng/ml) 12.3  12.2  2.1 27.5 37.0  22.0  >18.0 ng/ml No No No Yes Yes Yes <90.0 ng/ml Yes Yes Yes YesYes Yes Ratio of C_(max)/Dose Amount, /ml 3α-OH-5α-pregnan-20-one/ 6.2 ×10⁻⁸ 6.1 × 10⁻⁸ 1.1 × 10⁻⁸ 2.9 × 10⁻⁷ 1.9 × 10⁻⁷ 2.3 × 10⁻⁷Pregn-4-ene-3,20-dione >7.5 × 10⁻⁸/ml No No No Yes Yes Yes3α-OH-5b-pregnan-20-one/ 5.0 × 10⁻⁸ 5.3 × 10⁻⁸ 1.1 × 10⁻⁸ 2.8 × 10⁻⁷ 1.6× 10⁻⁷ 1.1 × 10⁻⁷ Pregn-4-ene-3,20-dione >5.0 × 10⁻⁸/ml No Yes No YesYes Yes (3α-OH-5a-pregnan-20-one + 1.1 × 10⁻⁷ 1.1 × 10⁻⁷ 2.2 × 10⁻⁸ 5.7× 10⁻⁷ 3.5 × 10⁻⁷ 2.2 × 10⁻⁷ 3α-OH-5b-pregnan-20-one)/Pregn-4-ene-3,20-dione >1.3 × 10⁻⁷/ml No No No Yes Yes YesAs a result, dosage forms of conventional compositions at 200 mg dose(Composition A, B, and C in Table 8) would not result in adequate levelsof neurosteroid essential for GABA_(A) modulating therapeutics. However,the dosage forms of the representative compositions (Composition D, E,and F in Table 8) resulted in efficient generation of levels adequatefor GABA_(A) modulating therapeutics with a lower dose or the equivalentdose. Furthermore, the dosage forms of the represented compositionsresulted in a higher ratio of C_(max)/dose of PAMs (e.g.,3α-OH-5α-pregnan-20-one and/or3α-OH-5b-pregnan-20-one)/Pregn-4-ene-3,20-dione than ones from theconventional compositions comprising crystalline form ofPregn-4-ene-3,20-dione (e.g., Composition A, B, and C).

Example 9—Clinical Study Example II for PK Measure

Assessment of effects of an inventive daily dose dosage form of thePregn-4-ene-3,20-dione composition (e.g., composition 6-1 in Table 6)relative to a prior art composition (e.g., composition A in Table 8) ina single dose can be conducted and the PK results and/or simulated datafrom clinical studies reported in the literature and studies conductedby Applicant as a single-dose crossover design, wherein volunteers wererandomized to six different treatments (40 mg, 80 mg, 120 mgPregn-4-ene-3,20-dione of composition A in Table 8, and 40 mg, 80 mg,120 mg Pregn-4-ene-3,20-dione of composition 6-1 in Table 6) withoutregard to meal. The pharmaceutical compositions comprisingPregn-4-ene-3,20-dione for this investigation are depicted in Table 8.The study population consisted of twelve (12) healthy non-smokingnon-hysterectomized postmenopausal women 45 to 65 years of age with aBMI of 18-32 kg/m².

The calculation of all pharmacokinetic parameters was based on theactual time for drug administration and blood sampling. The PK ofanalytes were measured using a chromatography combined mass spectrometrymethod (e.g., LC-MS/MS or GC-MS).

TABLE 9 Composition % w/w Component Composition A Composition 6-1Pregn-4-ene-3,20-dione 40.0 7.6 Edible Oil (e.g., peanut oil) 49.6 —Glyceryl monocaprylate — 82.9  (e.g., Capmul MCM C8) Alpha-tocopherol —4.6 Lecithin  0.4 — PEG-35 castor oil (e.g., — 4.9 Kolliphor EL) Othercarrier ingredients q.s. q.s. PK Parameters Treatment 1 2 3 4 5 6 Dailydose amount of 40 mg 80 mg 120 mg 40 mg 80 mg 120 mgPregn-4-ene-3,20-dione  Pregn-4-ene-3,20-dione C_(max), mean (ng/ml) 0.71.3 1.8 2.2  3.5  5.3 3α-OH-5β-pregnan-20-one C_(max), mean (ng/ml) 2.04.0 6.0 6.4 12.7 19.1 >6.0 ng/ml No No No Yes Yes Yes3α-OH-5α-pregnan-20-one C_(max), mean (ng/ml) 2.5 4.9 7.4 8.5 14.822.2 >8.0 ng/ml No No No Yes Yes Yes Ratio of C_(max)/Daily Dose Amount3α-OH-5α-pregnan-20-one/Pregn-4-ene-3,20-dione >7.5 × 10⁻⁸/ml No No NoYes Yes Yes 3α-OH-5β-pregnan-20-one/Pregn-4-ene- 3,20-dione >5.0 ×10⁻⁸/ml No No No Yes Yes Yes (3α-OH-5α-pregnan-20-one +3α-OH-5β-pregnan-20-one)/Pregn-4-ene-3,20-dione >1.3 × 10⁻⁷/ml No No NoYes Yes Yes

A dosage form of conventional compositions (e.g., composition A) atvarying doses failed to result in adequate levels of neurosteroidessential for GABA_(A) modulating therapeutics. However, the dosageforms of the representative inventive compositions (e.g., composition6-1) with various doses resulted in efficient generation of levelsadequate for GABA_(A) modulating therapeutics at the equivalent dose ofpregn-4-ene-3,20-dione of the conventional composition (e.g.,composition A). Furthermore, the dosage forms of the representedinventive compositions resulted in higher levels at the assessed dosethan ones obtained with composition A (micronizedpregn-4-ene-3,20-dione) at all study doses. This is, besidescompositional differences and/or release rate differences, possibly dueto a difference in predominance of containing crystalline form ofpregn-4-ene-3,20-dione in composition A versus predominance ofnon-crystalline forms (partially or fully solubilized and/or amorphousform of pregn-4-ene-3,20-dione) in the present composition (composition6-1).

Example 10—Clinical Study Design for Pharmacodynamic Effect in Womenwith Postpartum Depression

The pilot study entails a randomized, placebo-controlled, double-blindstudy with five arms to assess treatment potential in women with of CNSdepressive disorder, such as postpartum depression (PPD). The study armsare following as:

-   -   Treatment 1: A 45 mg daily dose capsule of        pregn-4-ene-3,20-dione of composition 6-3    -   Treatment 2: A 90 mg daily dose capsule of        pregn-4-ene-3,20-dione of composition 6-3    -   Treatment 3: A 20 mg daily dose capsule of        pregn-4-ene-3,20-dione of composition A (micronized        administration)    -   Treatment 4: A 200 mg daily dose capsule of        pregn-4-ene-3,20-dione of composition A (micronized        administration)    -   Treatment 5: A placebo capsule matching composition 6-3

Changes from baseline of HAM-D total, Saccadic Eye Movements, and MoodRating Score (MRS) can be measured to evaluate the effect of the testdrugs on treatment of CNS disorder in women with child-bearing age. Thetest drugs and placebo are administered in a fasted condition forfourteen days. Subjects are followed for 7 days following the last doseof study drug (Day 21).

The study can comprise 5 scheduled visits. Visit 1 is for screening anddetermining preliminary study eligibility. At Visit 2, Days 1-4,subjects are randomized and confined following study drug administrationthrough the morning on Day 4. Subjects undergo safety monitoring,intensive pharmacokinetic (PK) sampling of pregn-4-ene-3,20-dione andits metabolites, and monitoring depression symptoms. On Day 4, at thediscretion of the Principal Investigator (PI) subjects may leaveconfinement for the remainder of the study treatment (Day 15), or theconfinement stay may be extended. At Visits 3 and 4, Days 8 and 15respectively, subjects return to the clinic for safety monitoring andmeasuring of depression symptoms. A follow-up visit (Visit 5) occurs Day21, where End of Study (EOS) procedures is performed, and subjects exitfrom the trial.

Table 10 shows treatment effect of the present test composition(Composition 6-3) with two different daily doses and a conventionalcomposition (Composition A) compared to the placebo on change frombaseline in the HAM-D total score, Saccadic Eye Movements, and MoodRating Score at Days 8.

TABLE 10 Treatment effect of the present oral compositions on changes ofHAM-D, SEV, and MRS from baseline Saccadic Eye Movement & HAM-D TotalScore** Mood Rating Scale** Placebo- SEV Mean Mean adjusted (MeanSedation Calmness Daily baseline CBL^(†) mean CBL, (Mean (Mean TreatmentFormulation Dose score (Std. error) decrease deg/s)* CBL, mm) CBL, mm)Day 8 1 Composition 6-3 45 mg >20 −14.3 (1.2) >2 −30 −55 −18 2Composition 6-3 90 mg >20 −15.1 (1.2) >3 <−40 <−80 <−20 3 Composition A20 mg >20 −12.1 (1.1) <1 −22 −22 −11 (Micronized form) 4 Composition A200 mg  >20 −12.7 (1.2) <1 −25 −35 −15 (Micronized form) 5 Placebo — >20−12.0 (1.1) — −20 −20 −10 *Saccadic Eye Movement is measured by saccadiceye velocity (SEV) in deg/s. **Results were obtained by simulation basedon data from conducted clinical study results of HAM-D, Saccadic EyeVelocity (SEV), and Mood Rating Scale (MRS) reported in the literature.^(†)CBL: Change from baseline

As a result, the dosage form of the conventional composition at twodifferent doses of pregn-4-ene-3,20-dione (20 mg/day and 200 mg/day)upon micronized administration failed to show effective results fortreatment of CNS disorder (e.g., changes from baseline of HAM-D) and/orCNS activity (e.g., SEV and MRS), whereas the present representativecomposition (composition 6-3) with two different doses ofpregn-4-ene-3,20-dione (45 mg/day and 90 mg/day) suggested significantand meaningful changes towards a treatment for CNS depression disorderfrom baseline and greater changes compared to the placebo.

It is understood that the above-described various types of compositions,dosage forms methods and/or modes of applications are only illustrativeof various invention embodiments. Numerous modifications and alternativearrangements may be devised by those skilled in the art withoutdeparting from the spirit and scope of the present disclosure and theappended claims are intended to cover such modifications andarrangements. Thus, while invention embodiments have been describedabove with particularity and detail, it will be apparent to those ofordinary skill in the art that variations including, but not limited to,variations in size, materials, shape, form, function and manner ofoperation, assembly and use may be made without departing from theprinciples and concepts set forth herein.

1. A method of treating depression in a subject comprising orallyadministering to the subject an amount of a composition containing aneuroactive steroid (NAS) in an at least partially solubilized ornon-crystalline form that provides at least one of the following ratioscomprising: a C_(max) of 3α-OH-5β-pregnan-20-one/dose of said NAS offrom about 5.0×10⁻⁸/ml to about 2.5×10⁻⁶/ml, a C_(max) of3α-OH-5α-pregnan-20-one/dose of said NAS of from about 7.5×10⁻⁸/ml toabout 2.5×10⁻⁶/ml, a sum of C_(max) of (3α-OH-5α-pregnan-20-one and3α-OH-5β-pregnan-20-one)/dose of said NAS of from about 1.3×10⁻⁷/ml toabout 5.0×10⁻⁶/ml, a C_(max) of 3α-OH-5α-pregnan-20-one of greater thanabout 10 ng/ml, a C_(max) of 3α-OH-5β-pregnan-20-one of greater thanabout 6 ng/ml, a ratio of C_(max)/C_(max) of3α-OH-5α-pregnan-20-one/pregn-4-ene-3,20-dione of from about 2.0 toabout 50, a ratio of C_(max)/C_(max) of3α-OH-5β-pregnan-20-one/pregn-4-ene-3,20-dione of from about 1.0 toabout 50, and a ratio of C_(max)/C_(max) of (3α-OH-5α-pregnan-20-one and3α-OH-5β-pregnan-20-one)/pregn-4-ene-3,20-dione of from about 3 to about100, wherein said administration comprises a plurality of doses of saidcomposition administered at a frequency of at least four hours apart. 2.The method of claim 1, wherein said subject comprises a male, apremenopausal female, a perimenopausal female, a postmenopausal female,a pregnant female, or a postpartum female.
 3. The method of claim 1,wherein said NAS is combined with a pharmaceutically acceptable carrierto form an oral pharmaceutical composition comprising at least one offrom about 0.06 wt % to about 25 wt % and from about 3 wt % to 10 wt %of said NAS.
 4. The method of claim 3, wherein said carrier comprises atleast one of a hydrophilic additive, a lipophilic additive, and acombination thereof, and wherein said carrier comprises at least one ofalpha-tocopherol, glyceryl monocaprylate, glyceryl mono anddicaprylocaprate, propylene glycol monolaurate, propylene glycolmonocaprylate, peppermint oil, caprylic acid, oleic acid, castor oil,linoleic acid, steric acid, glyceryl distearate, sorbitan monolaurate,sorbitan monooleate, Linoleoyl Polyoxyl-6 glycerides, polyglyceryl3-oleate, lauroyl PEG-32 glycerides, oleoyl polyoxyl-6 glyceride,omega-3 esters/derivatives, PEG-35 castor oil, PEG-40 hydrogenatedcastor oil, polysorbate 80, polysorbate 20, polyglyceryl-10 monooleate,polyglyceryl-10 dioleate, polyglyceryl-10 monocaprylate, polyglyceryl-10dicaprylate, glyceryl-10 caprylate/caprate, glyceryl-10 monocaprate,caprylocaproyl polyoxyl-8 glyceride, tocopherol polyethylene glycolsuccinate, and a combination thereof and wherein said lipophilicadditive comprises at least one of alpha-tocopherol, glycerylmonocaprylate, glyceryl mono and dicaprylocaprate, propylene glycolmonolaurate, propylene glycol monocaprylate, peppermint oil, caprylicacid, oleic acid, castor oil, linoleic acid, steric acid, glyceryldistearate, sorbitan monolaurate, sorbitan monooleate, LinoleoylPolyoxyl-6 glycerides, polyglyceryl 3-oleate, lauroyl PEG-32 glycerides,oleoyl polyoxyl-6 glyceride, omega-3 esters/derivatives, and acombination thereof and wherein said hydrophilic additive comprises atleast one of PEG-35 castor oil, PEG-40 hydrogenated castor oil,polysorbate 80, polysorbate 20, polyglyceryl-10 monooleate,polyglyceryl-10 dioleate, polyglyceryl-10 monocaprylate, polyglyceryl-10dicaprylate, glyceryl-10 caprylate/caprate, glyceryl-10 monocaprate,caprylocaproyl polyoxyl-8 glyceride, tocopherol polyethylene glycolsuccinate, lauroyl PEG-32 glyceride, and a combination thereof.
 5. Themethod of claim 3, wherein from about 50% to about 100% of said NAS issolubilized in said carrier, and wherein said composition comprises anoral dosage form having at least one of from about 10 mg to about 400 mgof said NAS and from about 25 mg to 100 mg of said NAS.
 6. The method ofclaim 1, wherein a daily dose of said NAS comprises from about 10 mg toabout 3400 mg, and wherein said administration provides at least one of:a T_(max) for NAS in at least one of less than about 1.5 hours, lessthan about 2 hours, less than about 3 hours, and less than about 4 hourspost-administration; a reduction in C_(max) level to one half of aC_(max) level for NAS within at least one of about 1 hour, about 2hours, about 3 hours, about 4 hours, and about 5 hours post-T_(max); andtreatment that occurs within in at least one of less than about 1 hour,less than 2 hours, greater than about 2 hours, greater than 4 hours,greater than 8 hours, greater than about 24 hours, greater than about 2days, greater than about 3 days, greater than about 4 days, greater thanabout 5 days, greater than about 6 days, greater than about 7 days,greater than about 8 days, greater than about 14 days, and greater thanabout 28 days post-administration, and, wherein said administrationresults in a reduction of a 17-item HAM-D score in said subject ascompared to at least one of a placebo and a baseline by at least one ofabout 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9,about 10, about 10, about 11, about 12, about 13, about 14, about 15,about 16, about 17, about 18, about 16, and about 20 when measured atfrom about 3 days to about 30 days after commencement of treatment. 7.The method of claim 1, wherein said composition comprises at least oneof a tablet, a capsule, a caplet, a gelcap, a suspension, a solution, adrink, a gel, a syrup, a dispersion, an emulsion, a sprinkle, a lozenge,a microemulsion, a nanoemulsion, an elixir, a paste, a powder, and agranule, and an injectable, and wherein said drink comprises at leastone of a flavoring agent, a sweetener, an antimicrobial preservative, anantioxidant, and edible fat, and wherein said drink comprises a volumeof about 15 mL to about 90 mL, and wherein said drink comprises at leastone of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, of saidNAS.
 8. The method of claim 1, wherein said NAS comprisespregn-4-ene-3,20-dione or a metabolite thereof, and wherein saiddepression comprises PPD, and wherein at least one of said serum levelsis greater than a serum level resulting from a micronizedadministration.
 9. A method of treating depression comprising: orallyadministering to a subject an oral pharmaceutical composition comprisinga NAS in an at least partially solubilized or non-crystalline form and apharmaceutically acceptable carrier, which provides in said subject atleast one of: a serum level C_(max) of 3α-OH-5α-pregnan-20-one, a serumlevel C_(max) of 3α-OH-5β-pregnan-20-one, a serum level C_(avg) of3α-OH-5α-pregnan-20-one, and a serum level C_(avg) of3α-OH-5β-pregnan-20-one, wherein said administration comprises aplurality of doses of said composition administered at a frequency of atleast four hours apart.
 10. The method of claim 9, wherein said subjectcomprises a male or a female, and wherein said female comprises at leastone of a pregnant female, a postpartum female who has given birth withinat least one of one month, six months, and twelve months, apremenopausal female, a perimenopausal female, and a postmenopausalfemale.
 11. The method of claim 9, wherein said NAS comprises at leastone of from about 0.06 wt % to about 25 wt % and from about 3 wt % to 10wt % of said composition, and wherein said NAS comprises at least one ofa substantially non-crystalline form and a substantially solubilizedform.
 12. The method of claim 9, wherein said carrier comprises at leastone of a hydrophilic additive, a lipophilic additive, and a combinationthereof, and wherein said carrier comprises at least one ofalpha-tocopherol, glyceryl monocaprylate, glyceryl mono anddicaprylocaprate, propylene glycol monolaurate, propylene glycolmonocaprylate, peppermint oil, caprylic acid, oleic acid, castor oil,linoleic acid, steric acid, glyceryl distearate, sorbitan monolaurate,sorbitan monooleate, Linoleoyl Polyoxyl-6 glycerides, polyglyceryl3-oleate, lauroyl PEG-32 glycerides, oleoyl polyoxyl-6 glyceride,omega-3 esters/derivatives, PEG-35 castor oil, PEG-40 hydrogenatedcastor oil, polysorbate 80, polysorbate 20, polyglyceryl-10 monooleate,polyglyceryl-10 dioleate, polyglyceryl-10 monocaprylate, polyglyceryl-10dicaprylate, glyceryl-10 caprylate/caprate, glyceryl-10 monocaprate,caprylocaproyl polyoxyl-8 glyceride, tocopherol polyethylene glycolsuccinate, and a combination thereof, and wherein said lipophilicadditive comprises at least one of alpha-tocopherol, glycerylmonocaprylate, glyceryl mono and dicaprylocaprate, propylene glycolmonolaurate, propylene glycol monocaprylate, peppermint oil, caprylicacid, oleic acid, castor oil, linoleic acid, steric acid, glyceryldistearate, sorbitan monolaurate, sorbitan monooleate, LinoleoylPolyoxyl-6 glycerides, polyglyceryl 3-oleate, lauroyl PEG-32 glycerides,oleoyl polyoxyl-6 glyceride, omega-3 esters/derivatives, and acombination thereof, and wherein said hydrophilic additive comprises atleast one of PEG-35 castor oil, PEG-40 hydrogenated castor oil,polysorbate 80, polysorbate 20, polyglyceryl-10 monooleate,polyglyceryl-10 dioleate, polyglyceryl-10 monocaprylate, polyglyceryl-10dicaprylate, glyceryl-10 caprylate/caprate, glyceryl-10 monocaprate,caprylocaproyl polyoxyl-8 glyceride, tocopherol polyethylene glycolsuccinate, lauroyl PEG-32 glyceride, and a combination thereof.
 13. Themethod of claim 9, wherein a daily dose of said NAS comprises from about10 mg to about 3400 mg, and wherein said administration provides atleast one of: a T_(max) for at least one of 3α-OH-5α-pregnan-20-one,3α-OH-5β-pregnan-20-one, and a combination thereof in at least one ofless than about 1.5 hours, less than about 2 hours, less than about 3hours, and less than about 4 hours post-administration; a reduction inC_(max) level to one half of a C_(max) level for at least one of3α-OH-5α-pregnan-20-one and 3α-OH-5β-pregnan-20-one within at least oneof about 1 hour, about 2 hours, about 3 hours, about 4 hours, and about5 hours post-T_(max); and treatment that occurs within in at least oneof less than about 1 hour, less than 2 hours, greater than about 2hours, greater than 4 hours, greater than 8 hours, greater than about 24hours, greater than about 2 days, greater than about 3 days, greaterthan about 4 days, greater than about 5 days, greater than about 6 days,greater than about 7 days, greater than about 8 days, greater than about14 days, and greater than about 28 days post-administration, and whereinsaid administration results in a reduction of a 17-item HAM-D score insaid subject as compared to at least one of a placebo and a baseline byat least one of about 2, about 3, about 4, about 5, about 6, about 7,about 8, about 9, about 10, about 10, about 11, about 12, about 13,about 14, about 15, about 16, about 17, about 18, about 16, and about 20when measured at from about 3 days to about 30 days after commencementof treatment.
 14. The method of claim 9, wherein said compositioncomprises at least one of a tablet, a capsule, a caplet, a gelcap, asuspension, a solution, a drink, a gel, a syrup, a dispersion, anemulsion, a sprinkle, a lozenge, a microemulsion, a nanoemulsion, anelixir, a paste, a powder, and a granule, and an injectable, and whereinsaid drink comprises at least one of a flavoring agent, a sweetener, anantimicrobial preservative, an antioxidant, and edible fat, and whereinsaid drink comprises a volume of about 15 mL to about 90 mL, and whereinsaid drink comprises at least one of about 10 mg, about 20 mg, about 30mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg,about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg,about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg,about 800 mg, about 900 mg, of said NAS.
 15. The method of claim 9,wherein said NAS comprises pregn-4-ene-3,20-dione or a metabolitethereof, and wherein said depression comprises PPD, and wherein at leastone of said serum levels is greater than a serum level resulting from amicronized administration.
 16. A method of treating depressioncomprising: orally administering to a subject an oral pharmaceuticalcomposition comprising a NAS in an at least partially solubilized ornon-crystalline form and a pharmaceutically acceptable carrier, whichprovides in said subject a plurality of: a serum level C_(max) of3α-OH-5α-pregnan-20-one, a serum level C_(max) of3α-OH-5β-pregnan-20-one, a serum level C_(avg) of3α-OH-5α-pregnan-20-one, and a serum level C_(avg) of3α-OH-5β-pregnan-20-one, wherein said administration comprises aplurality of doses of said composition administered at a frequency of atleast four hours apart.
 17. The method of claim 16, wherein said subjectcomprises a male or a female, and wherein said female comprises at leastone of a pregnant female, a postpartum female who has given birth withinat least one of one month, six months, and twelve months, apremenopausal female, a perimenopausal female, and a postmenopausalfemale.
 18. The method of claim 16, wherein said NAS comprises at leastone of from about 0.06 wt % to about 25 wt % and from about 3 wt % to 10wt % of said composition, and wherein said NAS comprises at least one ofa substantially non-crystalline form and a substantially solubilizedform.
 19. The method of claim 16, wherein said carrier comprises atleast one of a hydrophilic additive, a lipophilic additive, and acombination thereof, and wherein said carrier comprises at least one ofalpha-tocopherol, glyceryl monocaprylate, glyceryl mono anddicaprylocaprate, propylene glycol monolaurate, propylene glycolmonocaprylate, peppermint oil, caprylic acid, oleic acid, castor oil,linoleic acid, steric acid, glyceryl distearate, sorbitan monolaurate,sorbitan monooleate, Linoleoyl Polyoxyl-6 glycerides, polyglyceryl3-oleate, lauroyl PEG-32 glycerides, oleoyl polyoxyl-6 glyceride,omega-3 esters/derivatives, PEG-35 castor oil, PEG-40 hydrogenatedcastor oil, polysorbate 80, polysorbate 20, polyglyceryl-10 monooleate,polyglyceryl-10 dioleate, polyglyceryl-10 monocaprylate, polyglyceryl-10dicaprylate, glyceryl-10 caprylate/caprate, glyceryl-10 monocaprate,caprylocaproyl polyoxyl-8 glyceride, tocopherol polyethylene glycolsuccinate, and a combination thereof, and wherein said lipophilicadditive comprises at least one of alpha-tocopherol, glycerylmonocaprylate, glyceryl mono and dicaprylocaprate, propylene glycolmonolaurate, propylene glycol monocaprylate, peppermint oil, caprylicacid, oleic acid, castor oil, linoleic acid, steric acid, glyceryldistearate, sorbitan monolaurate, sorbitan monooleate, LinoleoylPolyoxyl-6 glycerides, polyglyceryl 3-oleate, lauroyl PEG-32 glycerides,oleoyl polyoxyl-6 glyceride, omega-3 esters/derivatives, and acombination thereof, and wherein said hydrophilic additive comprises atleast one of PEG-35 castor oil, PEG-40 hydrogenated castor oil,polysorbate 80, polysorbate 20, polyglyceryl-10 monooleate,polyglyceryl-10 dioleate, polyglyceryl-10 monocaprylate, polyglyceryl-10dicaprylate, glyceryl-10 caprylate/caprate, glyceryl-10 monocaprate,caprylocaproyl polyoxyl-8 glyceride, tocopherol polyethylene glycolsuccinate, lauroyl PEG-32 glyceride, and a combination thereof.
 20. Themethod of claim 16, wherein a daily dose of said NAS comprises fromabout 10 mg to about 3400 mg, and wherein said administration providesat least one of: a T_(max) for at least one of 3α-OH-5α-pregnan-20-one,3α-OH-5β-pregnan-20-one, and a combination thereof in at least one ofless than about 1.5 hours, less than about 2 hours, less than about 3hours, and less than about 4 hours post-administration; a reduction inC_(max) level to one half of a C_(max) level for at least one of3α-OH-5α-pregnan-20-one and 3α-OH-5β-pregnan-20-one within at least oneof about 1 hour, about 2 hours, about 3 hours, about 4 hours, and about5 hours post-T_(max); and treatment that occurs within in at least oneof less than about 1 hour, less than 2 hours, greater than about 2hours, greater than 4 hours, greater than 8 hours, greater than about 24hours, greater than about 2 days, greater than about 3 days, greaterthan about 4 days, greater than about 5 days, greater than about 6 days,greater than about 7 days, greater than about 8 days, greater than about14 days, and greater than about 28 days post-administration, and whereinsaid administration results in a reduction of a 17-item HAM-D score insaid subject as compared to at least one of a placebo and a baseline byat least one of about 2, about 3, about 4, about 5, about 6, about 7,about 8, about 9, about 10, about 10, about 11, about 12, about 13,about 14, about 15, about 16, about 17, about 18, about 16, and about 20when measured at from about 3 days to about 30 days after commencementof treatment.
 21. The method of claim 16, wherein said compositioncomprises at least one of a tablet, a capsule, a caplet, a gelcap, asuspension, a solution, a drink, a gel, a syrup, a dispersion, anemulsion, a sprinkle, a lozenge, a microemulsion, a nanoemulsion, anelixir, a paste, a powder, and a granule, and an injectable, and whereinsaid drink comprises at least one of a flavoring agent, a sweetener, anantimicrobial preservative, an antioxidant, and edible fat, and whereinsaid drink comprises a volume of about 15 mL to about 90 mL, and whereinsaid drink comprises at least one of about 10 mg, about 20 mg, about 30mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg,about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg,about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg,about 800 mg, about 900 mg, of said NAS.
 22. The method of claim 16,wherein said NAS comprises pregn-4-ene-3,20-dione or a metabolitethereof, and wherein said depression comprises PPD, and wherein at leastone of said serum levels is greater than a serum level resulting from amicronized administration.
 23. A method of treating depression in asubject comprising orally administering to the subject a daily dose ofabout 10 mg to about 3400 mg of a composition containing a NAS in an atleast partially solubilized or non-crystalline form that provides atleast one of the following values comprising: a serum level C_(max) of3α-OH-5α-pregnan-20-one of greater than about 10 ng/ml, a serum levelC_(max) of 3α-OH-5β-pregnan-20-one of greater than about 6 ng/ml, aratio of C_(max)/C_(max) of3α-OH-5α-pregnan-20-one/pregn-4-ene-3,20-dione of from about 2.0 toabout 50, a ratio of C_(max)/C_(max) of3α-OH-5β-pregnan-20-one/pregn-4-ene-3,20-dione of from about 1.0 toabout 50, and a ratio of C_(max)/C_(max) of (3α-OH-5α-pregnan-20-one and3α-OH-5β-pregnan-20-one)/pregn-4-ene-3,20-dione of from about 3 to about100, wherein said administration comprises a plurality of doses of saidcomposition administered at a frequency of at least four hours apart.24. The method of claim 23, wherein said NAS is combined with apharmaceutically acceptable carrier to form an oral pharmaceuticalcomposition comprising at least one of from about 0.06 wt % to about 25wt % and from about 3 wt % to 10 wt % of said NAS, and wherein saidcarrier comprises at least one of a hydrophilic additive, a lipophilicadditive, and a combination thereof.
 25. The method of claim 24, whereinsaid carrier comprises at least one of alpha-tocopherol, glycerylmonocaprylate, glyceryl mono and dicaprylocaprate, propylene glycolmonolaurate, propylene glycol monocaprylate, peppermint oil, caprylicacid, oleic acid, castor oil, linoleic acid, steric acid, glyceryldistearate, sorbitan monolaurate, sorbitan monooleate, LinoleoylPolyoxyl-6 glycerides, polyglyceryl 3-oleate, lauroyl PEG-32 glycerides,oleoyl polyoxyl-6 glyceride, omega-3 esters/derivatives, PEG-35 castoroil, PEG-40 hydrogenated castor oil, polysorbate 80, polysorbate 20,polyglyceryl-10 monooleate, polyglyceryl-10 dioleate, polyglyceryl-10monocaprylate, polyglyceryl-10 dicaprylate, glyceryl-10caprylate/caprate, glyceryl-10 monocaprate, caprylocaproyl polyoxyl-8glyceride, tocopherol polyethylene glycol succinate, and a combinationthereof.
 26. The method of claim 24, wherein from about 50% to about100% of said NAS is solubilized in said carrier, and wherein saidcomposition comprises an oral dosage form having at least one of fromabout 10 mg to about 400 mg of said NAS and from about 25 mg to 100 mgof said NAS.
 27. The method of claim 23, wherein said administrationprovides at least one of: a T_(max) for NAS in at least one of less thanabout 1.5 hours, less than about 2 hours, less than about 3 hours, andless than about 4 hours post-administration; a reduction in C_(max)level to one half of a C_(max) level for NAS within at least one ofabout 1 hour, about 2 hours, about 3 hours, about 4 hours, and about 5hours post-T_(max); treatment that occurs within in at least one of lessthan about 1 hour, less than 2 hours, greater than about 2 hours,greater than 4 hours, greater than 8 hours, greater than about 24 hours,greater than about 2 days, greater than about 3 days, greater than about4 days, greater than about 5 days, greater than about 6 days, greaterthan about 7 days, greater than about 8 days, greater than about 14days, and greater than about 28 days after commencement of treatment;and a reduction of a 17-item HAM-D score in said subject as compared toat least one of a placebo and a baseline by at least one of about 2,about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10,about 10, about 11, about 12, about 13, about 14, about 15, about 16,about 17, about 18, about 16, and about 20 when measured at from about 3days to about 30 days after commencement of treatment
 28. The method ofclaim 23, wherein said composition comprises at least one of a tablet, acapsule, a caplet, a gelcap, a suspension, a solution, a drink, a gel, asyrup, a dispersion, an emulsion, a sprinkle, a lozenge, amicroemulsion, a nanoemulsion, an elixir, a paste, a powder, and agranule, and an injectable, and wherein said drink comprises at leastone of a flavoring agent, a sweetener, an antimicrobial preservative, anantioxidant, and edible fat, and wherein said drink comprises a volumeof about 15 mL to about 90 mL, and wherein said drink comprises at leastone of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, of saidNAS.
 29. The method of claim 23, wherein said depression comprisesperinatal depression, and wherein said subject comprises at least one ofa pregnant female and a female who has given birth within at least oneof one month, six months, and twelve months.
 30. The method of claim 23,wherein said NAS comprises pregn-4-ene-3,20-dione or a metabolitethereof, and wherein said depression comprises PPD, and wherein at leastone of said serum levels is greater than a serum level resulting from amicronized administration.